Current Research in Pharmacology and Drug Discovery 2 (2021) 100044

Contents lists available at ScienceDirect

Current Research in Pharmacology and Drug Discovery

journal homepage: www.journals.elsevier.com/current-research-in-pharmacology-
and-drug-discovery

Pharmacokinetic drug interactions of integrase strand transfer inhibitors

Chi-Hua Lu a, Edward M. Bednarczyk a, Linda M. Catanzaro a, Alyssa Shon b, Jia-Chen Xu a,
Qing Ma a, *
a
Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY, USA
b
Department of Medicine, Jacobs School of Medicine & Biomedical Sciences, University at Buffalo, Buffalo, NY, USA

A R T I C L E I N F O A B S T R A C T

Keywords: The integrase strand transfer inhibitor (INSTI)-containing regimens are currently considered as the first-line
Integrase strand transfer inhibitors treatment of human immunodeficiency virus (HIV) infection. Although possessing a common mechanism of ac-
Drug interactions tion to inhibit HIV integrase irreversibly to stop HIV replication cycle, the INSTIs, including raltegravir, elvite-
CYP450
gravir, dolutegravir, and bictegravir, differ in pharmacokinetic characteristics. While raltegravir undergoes
Transporter
biotransformation by the UDP-glucuronosyltransferases (UGTs), elvitegravir is primarily metabolized by cyto-
chrome P450 (CYP) 3A4 and co-formulated with cobicistat to increase its plasma exposure. The metabolism
pathways of dolutegravir and bictegravir are similar, both including CYP3A and UGT1A1, and both agents are
substrates to different drug transporters. Because of their differences in metabolism, INSTIs interact with other
medications differently through CYP enzymes and transporters as inducers or inhibitors. These drug interactions
may become an important consideration in the long-term clinical use because the life expectancy of people with
HIV (PWH) approaches to that of the general population. Also, common geriatric challenges such as multi-
morbidity and polypharmacy have been increasingly recognized in PWH. This review provides a summary of
pharmacokinetic interactions with INSTIs and future perspectives in implications of INSTI drug interactions.

1. Introduction 2010). There are four INSTIs currently approved by the Food and Drug
Administration (FDA) and available for clinic use including raltegravir
There were an estimated 38 million people living with the human (RAL), elvitegravir (EVG), dolutegravir (DTG), and bictegravir (BIC). The
immunodeficiency virus (HIV) at the end of 2019 globally (World Health superior efficacy of RAL, EVG, and DTG with similar or better safety
Organization, 2020). In the United States, there were an estimated 1.04 profiles compared to protease inhibitor (PI) - or non-nucleoside reverse
million adults and adolescents living with HIV and over 50% of people transcriptase inhibitor (NNRTI)-based regimens were demonstrated in
with HIV (PWH) were aged 50 and older in 2018 (Centers for Disease clinical trials and long-term real-world HIV management (Messiaen et al.,
Contr, 2018). With the advent of antiretroviral therapy (ART), the sur- 2013; Snedecor et al., 2019). The newest approved INSTI in 2018, BIC, is
vival and the quality of life in PWH have been dramatically improved well tolerated and has a relatively equivalent efficacy to DTG against
(Dionne, 2019). Integrase strand transfer inhibitors (INSTIs) represent INSTI-resistant mutants of the HIV-1 virus (Tsiang et al., 2016; Sax et al.,
one of nine drug categories currently available for the treatment of HIV 2017).
Type 1 (HIV-1) infection (Department of Health, 2020). In the most This review summarizes and compares human pharmacokinetics
recent guidelines from the Department of Health and Human Services (PK), drug-drug interactions of these INSTIs, and provides future per-
(DHHS) and the International Antiviral Society (IAS) - USA Panel, spectives in clinical implications of INSTI drug interactions.
INSTI-based combination ART has been recommended as the first-line
initial regimens for treatment-naïve PWH (Panel on Antiretroviral G, 2. Pharmacokinetics
2020; Saag et al., 2020).
INSTIs irreversibly inhibit HIV integrase to prevent the integration of Despite possessing a common mechanism of action, INSTIs differ in
virus DNA into host DNA to block the formation of the provirus and both structural and PK characteristics. This section summarizes major PK
propagation of the virus (Pandey and Grandgenett, 2008; Powderly, features of each INSTI, including absorption, distribution, and

* Corresponding author. University at Buffalo School of Pharmacy & Pharmaceutical Sciences, 315 Pharmacy Building, Buffalo, NY, 14214-8033, USA.
E-mail addresses: chihualu@buffalo.edu (C.-H. Lu), eb@buffalo.edu (E.M. Bednarczyk), lburow@buffalo.edu (L.M. Catanzaro), lyssash@buffalo.edu (A. Shon),
Jiachenx@buffalo.edu (J.-C. Xu), qingma@buffalo.edu (Q. Ma).

https://doi.org/10.1016/j.crphar.2021.100044
Received 8 March 2021; Received in revised form 4 August 2021; Accepted 5 August 2021
2590-2571/© 2021 Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
C.-H. Lu et al. Current Research in Pharmacology and Drug Discovery 2 (2021) 100044

metabolism which contribute to potential drug-drug interactions. The 2020; Genvoya, 2020; Yamada et al., 2018; Yonemura et al., 2018).
characteristics of INSTI drug metabolism based on the most recent Therefore, it has been recommended that EVG should be administered
manufacturers' package inserts and other recent published literature are with food to maintain the plasma concentration. It takes about 4 h to
summarized in Table 1. reach Tmax after taking EVG and it shows extensive protein binding
(99%) after absorption (Stribild, 2020; Genvoya, 2020). Unlike RAL, EVG
2.1. Raltegravir is converted to inactive metabolite primarily via hepatic and intestinal
cytochrome P450 (CYP) 3A4 enzymes and secondarily through UGT1A1
RAL is currently available in three dosage forms in the United States: and UGT1A3(Elliot et al., 2017). Since the CYP3A4 enzymes would
(1) film-coated tablets (400 mg and 600 mg); (2) chewable tablets decrease the plasma concentration of EVG extensively, co-administration
(100 mg and 25 mg); and (3) oral suspension (single-use packet of with a selective CYP3A inhibitor, COBI, may enhance EVG plasma
100 mg) (Isentress, 2020). exposure and prolongs its elimination half-life to allow once-daily
The 400 mg film-coated RAL tablet is rapidly absorbed with a median regimen (Shah et al., 2013; Ramanathan et al., 2011).
time to maximum plasma concentration (Tmax) approximately 3 h in the
fasted state (Krishna et al., 2018). The 600 mg tablet exhibits similar 2.3. Dolutegravir
systemic PK to the 400 mg tablet with a slightly shorter Tmax. The ab-
solute bioavailability of RAL has not been established due to the lack of a DTG was first approved by the FDA as a 50 mg oral use tablet in 2013
parenteral formulation (Podany et al., 2017). However, chewable tablet (Tivicay, 2020). As of October 2020, there are multiple products avail-
and oral suspension have higher oral bioavailability compared to the able containing DTG in the United States, including oral tablet (10 mg,
400 mg film-coated tablet (Isentress, 2020). Although food may increase 25 mg, and 50 mg), 50 mg tablets for oral suspension, two-drug combi-
the plasma concentration of RAL, it can be co-administered with or nation FDC tablets (DTG/lamivudine [3 TC]; DTG/rilpivirine [RPV]),
without food (Isentress, 2020; Podany et al., 2017; Brainard et al., 2011). and a three-drug combination tablet (DTG/3TC/abacavir [ABC]) (Tivi-
Following absorption, RAL is approximately 83% bound to human cay, 2020; Triumeq, 2020; Juluca, 2020; Dovato, 2020). DTG-based
plasma protein, mainly to albumin (Isentress, 2020; Barau et al., 2013). regimens could be used as an initial therapy for most people with HIV
The half-life of RAL is approximately 9 h (Isentress, 2020). The main (Panel on Antiretroviral G, 2020).
mechanism of clearance of RAL involves the Although the meal may increase the area under the concentration-
UDP-glucuronosyltransferases (UGTs), primarily the UGT1A1 isoform, time curve (AUC) of DTG up to 66% and the maximum concentration
which catalyzed the glucuronidation of a number of endogenous and of drug in plasma (Cmax) up to 67%, the increases were not expected to
exogenous substances (Kassahun et al., 2007; Elliot et al., 2017). In alter the clinical safety of the DTG (Podany et al., 2017; Song et al.,
addition, the polymorphisms of UGT1A1 may alter the plasma concen- 2012). Therefore, most DTG tablets may be taken with or without food,
tration of RAL (Wenning et al., 2009a). excepting the DTG/RPV FDC tablet per recommendations from the
manufacturer (Tivicay, 2020; Triumeq, 2020; Juluca, 2020; Dovato,
2020; Song et al., 2012). Moderate- or high-fat meals have been shown to
2.2. Elvitegravir increase the AUC and Cmax of both DTG and RPV (Mehta et al., 2020).
Taking RPV without food may decrease the plasma concentrations which
EVG is available in two different fixed-dose combination (FDC) tab- could potentially reduce the efficacy of the DTG/RPV tablet. Tmax of
lets from the same manufacturer (Stribild, 2020; Genvoya, 2020). The DTG were observed around 2–3 h post-dose and it displays highly bound
FDC tablets are a four-drug combination, including 150 mg EVG, 150 mg (
98.9%) to plasma proteins (Tivicay, 2020). DTG is a substrate of
of cobicistat (COBI), 200 mg of emtricitabine (FTC), and 300 mg of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), UGT1A3,
tenofovir disoproxil fumarate (TDF), or 10 mg of tenofovir alafenamide and UGT1A9 (Podany et al., 2017; Tivicay, 2020; Reese et al., 2013). It is
(TAF). Both of them are listed in the DHHS guideline as the recom- extensively metabolized by UGT1A1 with some contribution from CYP3A
mended initial HIV regimens if a one-pill, once-daily regimen is desired enzymes and the terminal elimination half-life (t½) of DTG is around 14 h
(Panel on Antiretroviral G, 2020). (Reese et al., 2013; Cottrell et al., 2013).
The absorption of EVG is significantly increased when it is taken with
food, including milk and protein-rich drink (Podany et al., 2017; Stribild, 2.4. Bictegravir

Table 1
BIC was approved in 2018 and it is only available in a three-drug
Characteristics of integrase strand transfer inhibitor drug metabolism.
combination (BIC/FTC/TAF) FDC tablet (Biktarvy, 2019). The efficacy
Medication Approval Substrate Inhibitor Inducer Reference and safety of BIC/FTC/TAF compared to other core regimens using on
Raltegravir 2007 UGT1A1 – – (Isentress, HIV treatment naïve and Treatment-experienced patients or switching
2020; Podany from other regimens to BIC/FTC/TAF were confirmed in multiple clinical
et al., 2017)
trials (Sax et al., 2017; Daar et al., 2018; Gallant et al., 2017; Iwuji et al.,
Elvitegravir 2012 CYP3A, – CYP2C9 (Podany et al.,
UGT1A1/3 2017; Stribild, 2020). Because of the durable virology efficacy, BIC/FTC/TAF is rec-
2020; ommended as an initial HIV therapy (Panel on Antiretroviral G, 2020).
Genvoya, The oral availability of BIC is around 70% and it could be taken with
2020) or without food even though the high-fat meals may increase the AUC
Dolutegravir 2013 CYP3A, OCT2, – (Podany et al.,
and Cmax by 24% and 13%, respectively (Biktarvy, 2019; Zeuli et al.,
UGT1A1/ MATE1 2017; Tivicay,
3/9, BCRP, 2020; 2019). The Tmax of BIC is between 2 and 4 h reflecting the administra-
P-gp Triumeq, tion of tablets with or without food. Following absorption, BIC is highly
2020; Juluca, bound to human plasma protein (>99%) and the median plasma half-life
2020; Dovato,
observed in healthy volunteers were approximately 18 h, which allows
2020)
Bictegravir 2018 CYP3A, OCT2, – Biktarvy
taking it once-daily (Zhang et al., 2017). Similar to DTG, the major
UGT1A1 MATE1 (2019) metabolism pathways of BIC are UGT1A1 with similar contribution from
CYP3A enzymes (Biktarvy, 2019).
Abbrev. BCRP, breast cancer resistance protein; CYP, cytochrome P450; MATE,
multidrug/toxin extrusion; OCT, organic cation transporter; P-gp, P-glycopro-
tein; UGT, UDP-glucuronosyltransferase.

2
C.-H. Lu et al. Current Research in Pharmacology and Drug Discovery 2 (2021) 100044

3. Drug-drug interactions metal-cation antacids and the INSTIs is predictable.

In a previous study, with the simultaneous antacid administration, the
Drug-drug interactions are commonly seen in other classes of ART Tmax of RAL 400 mg twice daily occurred 2 h sooner (p¼0.002), but had
such as PI-based regimens due to the inhibition of metabolizing enzymes no significant changes in Cmax and AUC0-12 (Kiser et al., 2010). Later on,
(Courlet et al., 2020). This section summarizes major drug-drug in- Krishna et al. reported findings from the once daily RAL 1200 mg
teractions of each INSTI, and the selection of clinical evidences are listed regimen co-administered with antacids containing Al3þ, Mg2þ, or Ca2þ
in Table 2. ions on HIV-infected patients (Krishna et al., 2016). When the calcium
carbonate (Ca2þ) was given concomitantly, the GMR for Cmax and AUC
3.1. Interactions with other antiretroviral medications from 0 to 24 h post-dose (AUC0-24) were 0.26 (0.21, 0.32), and 0.28
(0.24, 0.32). Although dose separation of antacids and RAL for 12 h could
RAL has been evaluated in combination with other HIV medicines. In ease the drug interactions, significant reductions in the trough concen-
the presence of efavirenz (EFV) 600 mg, a NNRTI, the PK of RAL 400 mg trations (C24) of RAL were observed: 0.43 (0.36, 0.51) taking Ca2þ ant-
once daily were weakly affected: the Cmax geometric mean ratio (GMR) acids, 0.42 (0.34, 0.52) taking Mg2þ/Al3þ antacids.
(90% confidence interval [CI]) was 0.64 (0.49, 1.28), and AUC from time The antacids would reduce the EVG plasma concentration of admin-
0 extrapolated to infinite time hour (AUC0-∞) was 0.64 (0.52, 0.80) istered concomitantly: Cmax [0.531 (0.468, 0.602)] and AUCτ [0.551
(Iwamoto et al., 2008a). When RAL and etravirine (ETR), another NNRTI, (0.504, 0.602)] (Ramanathan et al., 2013). Ramanathan et al. also
400/200 mg were used together twice daily, ETR only had a modest investigated the drug interactions between EVG and famotidine (H2-
effect on the PK of RAL (Anderson et al., 2008). Cmax was 0.89 (0.68, receptor antagonist), and omeprazole (proton pump inhibitors), and
1.15), and AUC from 0 to 12 h post-dose (AUC0-12) was 0.90 (0.68, 1.18). found no clinically relevant interactions from the study.
Although EFV and ETR are the known CYP inhibitors and inducers, the HIV-infected patients may take mineral supplements with their HIV
effects on UGT metabolism are minimal (Gong et al., 2019). medications. Song et al. reported that supplements containing Ca2þ and
Atazanavir (ATV) is a PI metabolized by CYP enzymes and it is an Fe2þ would significantly reduce the DTG plasma concentration by 39%
inhibitor of both CYP3A and UGT1A1 enzymes (Iwamoto et al., 2008b). [AUC0-∞, 0.61(0.47, 0.80)] and 54% [AUC0-∞, 0.46(0.35, 0.52)] under
In the exposure of ATV, it would moderately increase the plasma con- fasted conditions but no significant effected if taken separately or with a
centration of RAL 100 mg once daily: Cmax GMR was 1.53 (1.11, 2.12), moderate-fat meal (Song et al., 2015). A recent report observed that
and AUC0-∞ 1.72 (1.47, 2.02). A moderate increase of the plasma con- concomitant use of BIC and high dose of zinc (Zn2þ) supplementation
centration of RAL 400 mg twice daily was also found with ATV and ri- may lead to HIV treatment failure (Rock et al., 2020).
tonavir (ATV/r) co-administration [Cmax, 1.77 (1.39, 2.25); AUC0-12, In summary, co-administration with products containing divalent or
1.41 (1.12, 1.78)]. However, the extent of the increase of both combi- trivalent cations may decrease the plasma concentration of four INSTIs
nations was not believed to be clinically important. A similar increase of (Panel on Antiretroviral G, 2020). Antacids with Al3þ, Mg2þ or Ca2þ
plasma concentration was found in the combination of RAL and ATV should not be used with RAL 1200 mg; however, there is no limitation for
400/400 mg once daily regimen (Neely et al., 2010). The Cmax GMR the RAL 400 mg twice daily using with Ca2þ antacids. EVG should be
(95% CI) was 1.37 (0.62, 3.02), and AUC from time 0 to end of dosing given at least 2 h before or 6 h after taking products with polyvalent
interval (AUCτ) was 1.72 (0.79, 3.75). Coadministration of RAL and ATV cations. Dose separation strategy or taking with a meal are recommended
400/300 mg twice daily increase the AUC0-12 [1.536 (1.135, 2.081)] and with DTG and products containing multivalent cations. For BIC, dose
Cmax [1.394 (0.990, 1.964)] of RAL as well (Zhu et al., 2010). In sum- separation should be considered by taking products with Al3þ or Mg2þ,
mary, this interaction was most likely due to the inductive effect of EFV but antacids with Ca2þ could be taken with food. There is no dose
on UGT1A1, but the interaction was not clinically meaningful and did not adjustment needed when patients are using any INSTIs with H2 receptor
require dosage adjustment. antagonists and proton pump inhibitors.
EVG shares similarities to tipranavir (TPV) and darunavir (DRV) in
their elimination pathways, metabolized by CYP3A enzymes (Mathias 3.3. Interactions with enzyme inhibitors and inducers
et al., 2008). When EVG used with TPV, it would slightly increase the
Cmax [1.06 (0.89, 1.26)] and AUCτ [0.92 (0.79, 1.08)], respectively. The The CYP enzymes and UGT enzymes are responsible for drug meta-
increase of EVG concentration was observed in the study: Cmax [1.13 bolism (Kiang et al., 2005; Manikandan and Nagini, 2018). All INSTIs are
(1.03, 1.24)], and AUCτ [1.10 (0.99, 1.22)]. Gutierrez-Valencia et al. the substrates of UGT1A1 or CYP3A enzymes (Di Perri et al., 2019; Di
investigated the interaction between the DRV and the EVG/CO- Perri, 2019). Co-administration of INSTI with drugs that interrupt normal
BI/FTC/TDF single tablet on HIV-infected patients, and the results functions of those enzymes may be contraindicated or lead to potential
demonstrated that the concentration reduction effect of DRV on the EVG drug-drug interactions.
co-formulated tablet was not significant (p¼0.406) (Gutierrez-Valencia For example, rifampin, a well-known CYP enzyme inducer, demon-
et al., 2017). Thus, EVG may be combined with TPV or DRV without dose strated a reduction effect on the RAL plasma concentration because it also
adjustment. induced UGT enzymes (Wenning et al., 2009b). When RAL 400 mg twice
DTG was also tested with EFV or TPV because of the potential in- daily was concurrently used with rifampin 600 mg once daily, the Cmax
teractions affected by the CYP3A enzymes (Song et al., 2014). In the and AUC0-∞ of RAL were 0.62 (0.37, 1.04), and 0.60(0.39, 0.91),
DTG/EFV arm, the Cmax [0.608 (0.506, 0.730)] and AUCτ [0.431 (0.346, respectively. This study also showed that doubling the RAL dose did not
0.536)]. In the DTG/TPV arm, the Cmax [1.06 (0.89, 1.26)] and AUCτ overcome the rifampin reduction effect on the trough concentrations
[0.92 (0.79, 1.08)]. The results of the study showed that the decrease in (C12) of RAL: 0.47 (0.36, 0.61).
plasma DTG was likely in part due to the induction of CYP3A4 caused by In the presence of once daily rifampicin 600 mg, the decrease of DTG
the EFV and TPV. Thus, the dose adjustment may be necessary depends 50 mg was observed: Cmax 0.65 (0.55, 0.75), and AUC0-24 0.44 (0.37,
on the DTG dosage. 0.52) (Wang et al., 2019). Doubling the DTG dose could compensate the
Cmax, but not for the AUC0-24 [0.74 (0.64, 0.86)]. In a population-based
3.2. Interactions with antacids or mineral supplements study among 620 HIV patients, the model suggested that the Cmax and
AUC0-24 of DTG were 28% and 40 lower after 50 mg/12h with rifampicin
All INSTIs have the triad of heteroatoms responsible for metal che- compared with a standard dosage of 50 mg/24h without rifampicin
lation to bind to magnesium ions located at the catalytic site of the (Barcelo et al., 2019). In addition, the AUC0-24 after 100 mg/24h was
integrase enzyme to inhibit the activity of HIV-1 integrase (Kaur et al., 40% lower than the DTG standard dosage without rifampicin. Similar
2018; Markham, 2018) [Fig. 1]. Thus, the interaction between results were reported when DTG was used with other potent UGT/CYP3A

3
C.-H. Lu et al. Current Research in Pharmacology and Drug Discovery 2 (2021) 100044

Table 2
Selection of clinical evidences reporting the drug-drug interactions between integrase strand transfer inhibitors and other medications.
Year Study design Patient selection N Intervention GMR of PK parameters Ref.

Raltegravir

2008 Study I Double-blind  Healthy male 14 RAL 400 mg þ r 100 mg BID versus RAL 400 mg Cmax (μM) 0.76 (0.55, 1.04)a Iwamoto et al.
Placebo- within 30% of AUC0-∞ (μM ⋅h) 0.84 (0.70, (2008a)
controlled RCT IBW 1.01)a
Study II  18–45 years of 14 RAL 400 mg þ EFV 600 mg versus RAL 400 mg Cmax (μM) 0.64 (0.41, 0.98)a
age AUC0-∞ (μM ⋅h) 0.64 (0.52,
0.80)a
2008 – Open-label  Healthy subject 20 RAL 400 mg BID þ ETR 200 mg BID versus RAL Cmax (μM) 0.89 (0.68, 1.15)a Anderson et al. (2008)
trial within 30% of 400 mg BID AUC0-12 (μM ⋅h) 0.90 (0.68,
IBW 1.18)a
 18–45 years of
age
2008 Study I Double-blind  Healthy male 12 RAL 100 mg þ ATV 400 mg versus RAL 100 mg Cmax (μM) 1.53 (1.11, 2.12)a Iwamoto et al.
Placebo- AUC0-∞ (μM ⋅h) 1.72 (1.47, (2008b)
controlled RCT 2.02)a
Study II Open-label  Healthy subject 10 RAL 400 mg BID þ ATV/r 300/100 mg versus Cmax (μM) 1.24 (0.87, 1.77)a
trial RAL 400 mg BID AUC0-12 (μM ⋅h) 1.41 (1.12,
1.78)a
2009 Study I Open-label  Healthy subject 10 RAL 400 mg þ rifampin 600 mg versus RAL Cmax (μM) 1.24 (0.87, 1.77)a Wenning et al.
trial 400 mg AUC0-12 (μM ⋅h) 1.41 (1.12, (2009b)
1.78)a
Study II  Healthy subject 18 RAL 800 mg þ rifampin 600 mg versus RAL Cmax (μM) 1.24 (0.87, 1.77)a
400 mg AUC0-12 (μM ⋅h) 1.41 (1.12,
1.78)a
2010 – Open-label  Healthy subject 19 RAL 400 mg þ ATV 400 mg versus RAL 400 mg Cmax (ng/ml) 1.37 (0.62, Neely et al. (2010)
cross-over trial 
18 years of age 3.02)b
AUCτ (ng/ml ⋅h) 1.72 (0.79,
3.75)b
2010 – Open-label  Healthy subject 22 RAL 400 mg BID þ ATV 300 mg BID versus RAL Cmax (ng/ml) 1.394 (0.990, Zhu et al. (2010)
trial with BMI 18-32 400 mg BID 1.964)a
 18–45 years of AUC0-12 (ng/ml⋅h) 1.536
age (1.135, 2.081)a
2010 – Crossover RCT  Healthy subject 12 RAL 400 mg þ antacids versus RAL 400 mg Cmax (ng/ml) 1.53 (0.9, Kiser et al. (2010)
within 30% of 2.6)a
IBW,
50 kg AUC0-∞ (ng/ml ⋅h) 0.96
 18–60 years of (0.62, 1.5)a
age
2016 – Open-label  HIV-infected 20 RAL 1200 mg þ Ca2þ antacid 1000 mg (co- Cmax (ng/ml) 0.26 (0.21, Krishna et al. (2016)
trial patient administered) versus RAL 1200 mg 0.32)a

18 years of age AUC0-∞ (ng/ml ⋅h) 0.28
(0.24, 0.32)a
RAL 1200 mg þ Mg2þ/Al3þ antacid 1600/ Cmax (ng/ml) 0.86 (0.65,
1600 mg (þ12 h) versus RAL 1200 mg 1.15)a
AUC0-24 (ng/ml ⋅h) 0.86
(0.73, 1.03)a
RAL 1200 mg þ Ca2þ antacid 1000 mg (þ12 h) Cmax (ng/ml) 0.98 (0.81,
versus RAL 1200 mg 1.17)a
AUC0-24 (ng/ml ⋅h) 0.90
(0.80, 1.03)a

Elvitegravir

2008 Study I Open-label  Healthy subject 34 EVG 200 mg þ TPV/r 500/200 mg BID versus Cmax (ng/ml) 1.06 (0.894, Mathias et al. (2008)
trial with BMI 19-30 EVG/r 200/100 mg 1.26)a
 18–45 years of AUCτ (ng/ml ⋅h) 0.924
age (0.787, 1.08)a
Study II 33 EVG 125 mg þ DRV/r 600/100 mg BID versus Cmax (ng/ml) 1.13 (1.03,
EVG//r 125/100 mg 1.24)a
AUCτ (ng/ml ⋅h) 1.10
(0.991, 1.22)a
2013 Open-label  Healthy subject 13 EVG/r 50/100 mg þ antacids (co-administered) Cmax (ng/ml) 0.531 (0.468, Ramanathan et al.
cross-over trial with versus EVG/r 50/100 mg 0.602)a (2013)
 18–45 years of AUCτ (ng/ml ⋅h) 0.551
age (0.504, 0.602)a
22 EVG/COBI 150/150 mg þ omeprazole (2 h Cmax (ng/ml) 1.16 (1.04,
prior) versus EVG/COBI 150/150 mg 1.30)a
AUCτ (ng/ml ⋅h) 1.10 (1.02,
1.19)a
EVG/COBI 150/150 mg þ omeprazole (12 h Cmax (ng/ml) 1.03 (0.919,
after) versus EVG/COBI 150/150 mg 1.15)a
AUCτ (ng/ml ⋅h) 1.05
(0.929, 1.18)a
26 EVG/COBI 150/150 mg þ famotidine (12 h Cmax (ng/ml) 1.02 (0.894,
after) versus EVG/COBI 150/150 mg 1.17)a
(continued on next page)

4
C.-H. Lu et al. Current Research in Pharmacology and Drug Discovery 2 (2021) 100044

Table 2 (continued )
Year Study design Patient selection N Intervention GMR of PK parameters Ref.

AUCτ (ng/ml ⋅h) 1.03

(0.949, 1.13)a
EVG/COBI 150/150 mg þ famotidine (co- Cmax (ng/ml) 1.00 (0.917,
administered) versus EVG/COBI 150/150 mg 1.10)a
AUCτ (ng/ml ⋅h) 1.03
(0.981, 1.08)a
2017 – Clinical trial  HIV infected 88 Group A: EVG 150 mg þ DRV 800 mg No GMR reported in the Gutierrez-Valencia
patient Group B: EVG 150 mg study et al. (2017)
Group C: DRV/COBI 800/150 mg Group A EVG concentration
was 6.6% lower than group
B (p¼0.406)

Dolutegravir

2014 Study Open-label  Healthy subject 12 DTG 50 mg þ EFV 600 mg versus DTG 50 mg Cmax (μg/ml) 0.608 (0.506, Song et al. (2014)
I trial 0.730)a
AUCτ (μg/ml ⋅h) 0.431
(0.346, 0.536)a
Study 18 DTG 50 mg þ TPV/r 500/200 mg versus DTG Cmax (μg/ml) 0.535 (0.500,
II 50 mg 0.572)a
AUCτ (μg/ml ⋅h) 0.409
(0.379, 0.443)a
2015 – Open-label  Healthy subject 21 DTG 50 mg þ calcium carbonate 1200 mg Cmax 0.63 (0.50, 0.81)a Song et al. (2015)
trial (fasted) versus DTG 50 mg (fasted) AUC0-∞ 0.61 (0.47, 0.80)a
DTG 50 mg þ calcium carbonate 1200 mg (with Cmax 1.07 (0.83, 1.38)a
meal) versus DTG 50 mg (fasted) AUC0-∞ 1.09 (0.84, 1.43)a
DTG 50 mg þ calcium carbonate 1200 mg (2 h Cmax 1.00 (0.78, 1.29)a
prior) versus DTG 50 mg (fasted) AUC0-∞ 0.94 (0.72, 1.23)a
DTG 50 mg þ calcium carbonate 1200 mg (with Cmax 1.70 (1.32, 2.18)a
meal) versus DTG 50 mg þ calcium carbonate AUC0-∞ 1.78 (1.36, 2.33)a
1200 mg (fasted)
DTG 50 mg þ ferrous fumarate 324 mg (fasted) Cmax 0.43 (0.35, 0.52)a
versus DTG 50 mg (fasted) AUC0-∞ 0.46 (0.38, 0.56)a
DTG 50 mg þ ferrous fumarate 324 mg (with Cmax 1.03 (0.84, 1.26)a
meal) versus DTG 50 mg (fasted) AUC0-∞ 0.98 (0.81, 1.20)a
DTG 50 mg þ ferrous fumarate 324 mg (2 h Cmax 0.99 (0.81, 1.21)a
prior) versus DTG 50 mg (fasted) AUC0-∞ 0.95 (0.77, 1.15)a
DTG 50 mg þ ferrous fumarate 324 mg (with Cmax 2.41 (1.97, 2.94)a
meal) versus DTG 50 mg þ ferrous fumarate AUC0-∞ 2.14(1.76, 2.61)a
324 mg (fasted)
2016 – Open-label  Healthy subject 14 DTG 50 mg þ carbamazepine 300 mg BID Cmax (μg/ml) 0.666 (0.610, Song et al. (2016a)
trial versus DTG 50 mg 0.726)a
AUCτ (μg/ml ⋅h) 0.512
(0.477, 0.549)a
2019 – Open-label  Healthy subject 14 DTG 100 mg þ rifampicin 600 mg versus DTG Cmax 1.68 (1.43, 1.97)a Wang et al. (2019)
trial with BMI 18-35 50 mg þ rifampicin 600 mg AUC0-24 1.70 (1.49, 1.95)a
 18–60 years of DTG 50 mg þ rifampicin 600 mg versus DTG Cmax 0.65 (0.55, 0.75)a
age 50 mg AUC0-24 0.44 (0.37, 0.52)a
DTG 100 mg þ rifampicin 600 mg versus DTG Cmax 0.64 (0.55, 0.74)a
100 mg AUC0-24 0.42 (0.35, 0.50)a
DTG 100 mg þ rifampicin 600 mg versus DTG Cmax 1.09 (0.97, 1.21)a
50 mg AUC0-24 0.74 (0.64, 0.86)a
2019c – Model  HIV infected 521 DTG 50 mg BID þ rifampicin 600 mg versus Cmax 0.72 Barcelo et al. (2019)
simulation patient DTG 50 mg QD AUC0-24 0.60
study DTG 100 mg QD þ rifampicin 600 mg versus Cmax 1.24
DTG 50 mg QD AUC0-24 0.60
DTG 100 mg BID þ rifampicin 600 mg versus Cmax 1.44
DTG 50 mg QD AUC0-24 1.20

ATV, atazanavir; AUC0-12, area under the concentration-time curve from time 0–12 h; AUC0-∞, area under the concentration-time curve from time 0 extrapolated to
infinite time hour; BID, twice daily; BMI, body mass index; COBI, cobistat; DRV, darunavir; DTG, dolutegravir; EFV, efavirenz; ETR, etravirine; EVG, elvitegravir; GMR,
Geometrical Mean Radius; IBW, ideal body weight; PK, pharmacokinetics; r, ritonavir; RAL, raltegravir; RCT, randomized clinical trial; QD, once daily; TPV, tipranavir.
a
90% confidence interval (CI).
b
95% CI.
c
No 90%CI reported in the study.

such as carbamazepine (Song et al., 2016a). DTG/carbamazepine versus susceptible to drug-drug interactions via CYP3A4 (e.g. contraindicated
DTG alone were 0.67 (0.61, 0.73), and 0.51 (0.48, 0.55) for the Cmax, and with rifampin) (Biktarvy, 2019).
AUCτ, respectively. Based on the experiences from previous studies, patients treated with
Since the EVG is primarily metabolized by CYP3A4, it is contra- INSTIs and potent enzymes inhibitors/inducers may benefit from thera-
indicated to used EVG with a drug that also undergo CYP3A4 metabolism peutic drug monitoring and individualized dosage. In addition, a Swiss
extensively (e.g. alfuzosin) which may increase its concentration and study found that unboosted INSTIs (RAL, DTG, and BIC) had lower
lead to severe adverse effects, or used with a strong CYP3A4 enzyme chance to cause suboptimal response compared to PI-based regimens
inducer (e.g. rifampin and carbamazepine) which may lower the level of (Courlet et al., 2020).
EVG (Panel on Antiretroviral G, 2020). Compared to DTG, BIC is more

5
C.-H. Lu et al. Current Research in Pharmacology and Drug Discovery 2 (2021) 100044

Fig. 1. Chemical structures of integrase strand transfer inhibitor. Adapted from PubChem.

3.4. Interactions with drug transporters increased risk of poor health outcomes because of the aging related
comorbidities (Centers for Disease Contr, 2018; Saag et al., 2020).
Drug transporters such as P-gp, BCRP, organic cation transporters With the coexisting comorbidities, the risk of drug-drug interactions
(OCTs), and multidrug/toxin extrusions (MATEs) are determinants of increased due to polypharmacy (commonly defined as the concurrent
drug disposition by affecting the pharmacokinetics of drugs (Liu, 2019; administration of
5 medications) among elderly patients (Masnoon
Gessner et al., 2019). Screening the new molecular entities as substrates et al., 2017). Physiological changes related to aging may affect phar-
or inhibitors of transporters in the drug development process is now a macokinetics putting elderly patients with or without HIV at risk of
common practice because serious drug-drug interactions may occur due experiencing drug-drug interactions. In HIV care settings, polypharmacy
to the effects of transporters (Gessner et al., 2019). BIC and DTG are often refers to non-HIV medications given in addition to standard ARTs
inhibitors of OCT2 and MATE1; DTG is also the substrates of P-gp and (Back and Marzolini, 2020). It is common to see that the total number of
BCRP (Triumeq, 2020; Biktarvy, 2019; Di Perri, 2019). Therefore, BIC medications used in HIV patients is much higher than those patients
and DTG may increase plasma concentrations of drugs eliminated via without HIV and increases the risk of experiencing polypharmacy related
OCT2 or MATE1 such as dofetilide and metformin (Triumeq, 2020; drug-drug interactions among those patients. A recent study showed that
Biktarvy, 2019). Due to the narrow therapeutic index of dofetilide, it is about 1/3 of elderly had complex ART regimens, and inappropriate
contraindicated to used dofetilide with BIC or DTC concurrently. Previ- medications were found in 14% elderly PLWH (Courlet et al., 2019).
ous studies showed that both BIC and DTG increased metformin plasma Thus, caution is needed when prescribing medications in those pop-
exposure in healthy adults and the dose adjustment of metformin is ulations. As today, there is no large population-based data from clinical
recommended to maintain optimal blood glucose control (Song et al., trials or PK studies for INSTIs to determine the efficacy and safety in the
2016b; Custodio et al., 2017). There were no severe adverse effects such elderly (Isentress, 2020; Stribild, 2020; Genvoya, 2020; Tivicay, 2020;
as lactic acidosis reported when dolutegravir and metformin were Triumeq, 2020; Juluca, 2020; Dovato, 2020; Biktarvy, 2019). Dose
co-prescribed to HIV patients but evaluating concurrent use of metformin adjustment for other concomitant non-HIV medicines may be necessary
and DTG case by case should still be considered (Masich et al., 2017; in elderly patients reflecting the greater frequency of decreased hepatic,
Naccarato et al., 2017). renal, or cardiac function.

4. Aging and polypharmacy 5. Conclusion & perspectives

The life expectancy of people living with HIV is approaching that of Potent antiretroviral combinations have been established as the gold
the general population because of the high efficacy and safety of ARTs standard in the DHHS and IAS guidelines (Panel on Antiretroviral G,
(Marcus et al., 2020). The estimated average lifespan in patients who 2020; Saag et al., 2020). The mechanism of INSTIs blocks HIV integrase
achieved viral suppression and maintained CD4þ cell count
350 cells/μl to insert viral DNA into the DNA of the host CD4 cell to prevent HIV from
is about 80 years (May et al., 2014). In 2018, over half of people living replicating demonstrating high potent of efficacy for HIV treatment.
with HIV were aged 50 and older in the United States, and they are at Although possessing a common mechanism of action to inhibit HIV

6
C.-H. Lu et al. Current Research in Pharmacology and Drug Discovery 2 (2021) 100044

integrase, the INSTIs, can be distinguished on the basis of pharmacoki- label, multicentre, phase 3, non-inferiority trial. Lancet HIV 5 (7), e347–e356.
https://doi.org/10.1016/s2352-3018(18)30091-2. Epub 2018/06/22.
netic differences, resulting in different dose frequency, combinations and
U.S. Department of Health and Human Services, 2020 October 20. FDA-approved HIV
concern of drug-drug interactions. Medicines. https://hivinfo.nih.gov/understanding-hiv/fact-sheets/fda-approved-hiv-
The clinical significance of INSTI drug interactions needs to be eval- medicines.
uated case by case, as large inter-individual variability exists. In the Di Perri, G., 2019. Clinical pharmacology of the single tablet regimen bictegravir/
emtricitabine/tenofovir alafenamide (BIC/FTC/TAF). Infez Med 27 (4), 365–373.
meantime, the metabolism pathways are slightly different from each Epub 2019/12/18.
INSTIs. For example, RAL only undergoes via the UGT system; EVG has to Di Perri, G., Calcagno, A., Trentalange, A., Bonora, S., 2019. The clinical pharmacology of
use with CYP3A booster; DTG and BIC are metabolized by CYP3A and integrase inhibitors. Expet Rev. Clin. Pharmacol. 12 (1), 31–44. https://doi.org/
10.1080/17512433.2019.1553615. Epub 2018/12/05.
UGT system with a different contribution. With the life expectancy Dionne, B., 2019. Key principles of antiretroviral pharmacology. Infect Dis Clin North Am
increased in HIV patients, a better understanding of the clinical phar- 33 (3), 787–805. https://doi.org/10.1016/j.idc.2019.05.006. Epub 2019/08/10.
macology of these agents in the elderly population is crucial to the Dovato®[package Insert], August 2020. Viiv Healthcare, Research Triangle Park, NC.
Elliot, E., Chirwa, M., Boffito, M., 2017. How recent findings on the pharmacokinetics and
development of rational therapeutic regimens and dosage adjustment pharmacodynamics of integrase inhibitors can inform clinical use. Curr. Opin. Infect.
due to limited data. Dis. 30 (1).
Gallant, J., Lazzarin, A., Mills, A., Orkin, C., Podzamczer, D., Tebas, P., et al., 2017.
Bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir, abacavir,
CRediT authorship contribution statement and lamivudine for initial treatment of HIV-1 infection (GS-US-380-1489): a double-
blind, multicentre, phase 3, randomised controlled non-inferiority trial. Lancet (Lond.
Chi-Hua Lu: Conceptualization, data collection and analysis, Writing Engl.) 390 (10107), 2063–2072. https://doi.org/10.1016/s0140-6736(17)32299-7.
Epub 2017/09/05.
– original draft, preparation. Edward M. Bednarczyk: discussion, Genvoya® [package Insert], December 2020. Gilead Sciences, Inc., Foster City, CA.
Writing – review & editing. Linda M. Catanzaro: discussion, Writing – Gessner, A., K€ onig, J., Fromm, M.F., 2019. Clinical aspects of transporter-mediated drug-
review & editing. Alyssa Shon: discussion, Writing – review & editing. drug interactions. Clin. Pharmacol. Ther. 105 (6), 1386–1394. https://doi.org/
10.1002/cpt.1360. Epub 2019/01/17.
Jia-Chen Xu: discussion, Writing – review & editing. Qing Ma:
Gong, Y., Haque, S., Chowdhury, P., Cory, T.J., Kodidela, S., Yallapu, M.M., et al., 2019.
Conceptualization, Writing – review & editing. Pharmacokinetics and pharmacodynamics of cytochrome P450 inhibitors for HIV
treatment. Expet Opin. Drug Metabol. Toxicol. 15 (5), 417–427. https://doi.org/
10.1080/17425255.2019.1604685. Epub 2019/04/20.
Declaration of competing interest Gutierrez-Valencia, A., Benmarzouk-Hidalgo, O.J., Llaves, S., Fernandez-Magdaleno, T.,
Espinosa, N., Viciana, P., et al., 2017. Pharmacokinetic interactions between
The authors declare the following financial interests/personal re- cobicistat-boosted elvitegravir and darunavir in HIV-infected patients. J. Antimicrob.
Chemother. 72 (3), 816–819. https://doi.org/10.1093/jac/dkw487. Epub 2016/12/
lationships which may be considered as potential competing interests: 22.
Dr. Qing Ma is currently supported in part by NIH grant R01AG063659 Isentress® [package Insert], July 2020. Merck & Co., Inc., Whitehouse Station, NJ.
and investigator-initiated research grants from Merck, United State, and Iwamoto, M., Wenning, L.A., Petry, A.S., Laethem, M., De Smet, M., Kost, J.T., et al.,
2008a. Minimal effects of ritonavir and efavirenz on the pharmacokinetics of
Gilead Sciences. raltegravir. Antimicrob. Agents Chemother. 52 (12), 4338–4343. https://doi.org/
10.1128/aac.01543-07. Epub 2008/10/08.
References Iwamoto, M., Wenning, L.A., Mistry, G.C., Petry, A.S., Liou, S.Y., Ghosh, K., et al., 2008b.
Atazanavir modestly increases plasma levels of raltegravir in healthy subjects. Clin.
Infect. Dis. : Off. Publ. Infect. Dis. Soc. Am. 47 (1), 137–140. https://doi.org/
Anderson, M.S., Kakuda, T.N., Hanley, W., Miller, J., Kost, J.T., Stoltz, R., et al., 2008.
10.1086/588794. Epub 2008/06/03.
Minimal pharmacokinetic interaction between the human immunodeficiency virus
Iwuji, C.C., Churchill, D., Bremner, S., Perry, N., To, Y., Lambert, D., et al., 2020. A phase
nonnucleoside reverse transcriptase inhibitor etravirine and the integrase inhibitor
IV randomised, open-label pilot study to evaluate switching from protease-inhibitor
raltegravir in healthy subjects. Antimicrob. Agents Chemother. 52 (12), 4228–4232.
based regimen to Bictegravir/Emtricitabine/Tenofovir Alafenamide single tablet
https://doi.org/10.1128/aac.00487-08. Epub 2008/10/08.
regimen in Integrase inhibitor-naïve, virologically suppressed HIV-1 infected adults
Back, D., Marzolini, C., 2020. The challenge of HIV treatment in an era of polypharmacy.
harbouring drug resistance mutations (PIBIK study): study protocol for a randomised
J. Int. AIDS Soc. 23 (2). https://doi.org/10.1002/jia2.25449 e25449-e.
trial. BMC Infect. Dis. 20 (1), 524. https://doi.org/10.1186/s12879-020-05240-y.
Barau, C., Furlan, V., Yazdanpanah, Y., Fagard, C., Molina, J.M., Taburet, A.M., et al.,
Epub 2020/07/22.
2013. Characterization of binding of raltegravir to plasma proteins. Antimicrob.
Juluca®[package Insert], July 2020. Viiv Healthcare, Research Triangle Park, NC.
Agents Chemother. 57 (10), 5147–5150. https://doi.org/10.1128/aac.00625-13.
Kassahun, K., McIntosh, I., Cui, D., Hreniuk, D., Merschman, S., Lasseter, K., et al., 2007.
Epub 2013/07/17.
Metabolism and disposition in humans of raltegravir (MK-0518), an anti-AIDS drug
Barcelo, C., Aouri, M., Courlet, P., Guidi, M., Braun, D.L., Günthard, H.F., et al., 2019.
targeting the human immunodeficiency virus 1 integrase enzyme. Drug Metab.
Population pharmacokinetics of dolutegravir: influence of drug-drug interactions in a
Dispos. 35 (9), 1657–1663. https://doi.org/10.1124/dmd.107.016196. Epub 2007/
real-life setting. J. Antimicrob. Chemother. 74 (9), 2690–2697. https://doi.org/
06/27.
10.1093/jac/dkz217. Epub 2019/05/24.
Kaur, M., Rawal, R.K., Rath, G., Goyal, A.K., 2018. Structure based drug design: clinically
Biktarvy®[package Insert], August 2019. Gilead Sciences, Inc., Foster City, CA.
relevant HIV-1 integrase inhibitors. Curr. Top. Med. Chem. 18 (31), 2664–2680.
Brainard, D.M., Friedman, E.J., Jin, B., Breidinger, S.A., Tillan, M.D., Wenning, L.A., et al.,
https://doi.org/10.2174/1568026619666190119143239. Epub 2019/01/20.
2011. Effect of low-, moderate-, and high-fat meals on raltegravir pharmacokinetics.
Kiang, T.K., Ensom, M.H., Chang, T.K., 2005. UDP-glucuronosyltransferases and clinical
J. Clin. Pharmacol. 51 (3), 422–427. https://doi.org/10.1177/0091270010367652.
drug-drug interactions. Pharmacol. Ther. 106 (1), 97–132. https://doi.org/10.1016/
Epub 2010/05/12.
j.pharmthera.2004.10.013. Epub 2005/03/23.
Centers for Disease Control and Prevention, 2018. HIV Surveillance Report (Updated);
Kiser, J.J., Bumpass, J.B., Meditz, A.L., Anderson, P.L., Bushman, L., Ray, M., et al., 2010.
vol. Published May 2020 [cited 2020 September 17]. http://www.cdc.gov/hiv/li
Effect of antacids on the pharmacokinetics of raltegravir in human immunodeficiency
brary/reports/hiv-surveillance.html.
virus-seronegative volunteers. Antimicrob. Agents Chemother. 54 (12), 4999–5003.
Cottrell, M.L., Hadzic, T., Kashuba, A.D., 2013. Clinical pharmacokinetic,
https://doi.org/10.1128/aac.00636-10. Epub 2010/10/06.
pharmacodynamic and drug-interaction profile of the integrase inhibitor
Krishna, R., East, L., Larson, P., Valiathan, C., Butterfield, K., Teng, Y., et al., 2016. Effect
dolutegravir. Clin. Pharmacokinet. 52 (11), 981–994. https://doi.org/10.1007/
of metal-cation antacids on the pharmacokinetics of 1200 mg raltegravir. J. Pharm.
s40262-013-0093-2. Epub 2013/07/05.
Pharmacol. 68 (11), 1359–1365. https://doi.org/10.1111/jphp.12632. Epub 2016/
Courlet, P., Marzolini, C., Cavassini, M., Battegay, M., Guidi, M., Alves Saldanha, S., et al.,
10/21.
March . Polypharmacy, Inappropriate Drugs & Drug-Drug Interactions in HIV-
Krishna, R., Rizk, M.L., Larson, P., Schulz, V., Kesisoglou, F., Pop, R., 2018. Single- and
Infected Elderly. Conference on Retroviruses and Opportunistic Infections. Seattle,
multiple-dose pharmacokinetics of once-daily formulations of raltegravir. Clin
WA.
Pharmacol Drug Dev 7 (2), 196–206. https://doi.org/10.1002/cpdd.358. Epub
Courlet, P., Livio, F., Alves Saldanha, S., Scherrer, A., Battegay, M., Cavassini, M., et al.,
2017/04/19.
2020. Real-life management of drug–drug interactions between antiretrovirals and
Liu, X., 2019. Transporter-mediated drug-drug interactions and their significance. Adv.
statins. J. Antimicrob. Chemother. 75 (7), 1972–1980. https://doi.org/10.1093/jac/
Exp. Med. Biol. 1141, 241–291. https://doi.org/10.1007/978-981-13-7647-4_5.
dkaa099.
Epub 2019/10/02.
Custodio, J., West, S., Yu, A., Martin, H., Graham, H., Quirk, E., et al., 2017. Lack of
Manikandan, P., Nagini, S., 2018. Cytochrome P450 structure, function and clinical
clinically relevant effect of bictegravir (BIC, B) on metformin (MET)
significance: a review. Curr. Drug Targets 19 (1), 38–54. https://doi.org/10.2174/
pharmacokinetics (PK) and pharmacodynamics (PD). Open Forum Infect. Dis. 4
1389450118666170125144557. Epub 2017/01/27.
(Suppl. 1), S429–S. https://doi.org/10.1093/ofid/ofx163.1082.
Marcus, J.L., Leyden, W.A., Alexeeff, S.E., Anderson, A.N., Hechter, R.C., Hu, H., et al.,
Daar, E.S., DeJesus, E., Ruane, P., Crofoot, G., Oguchi, G., Creticos, C., et al., 2018.
2020. Comparison of overall and comorbidity-free life expectancy between insured
Efficacy and safety of switching to fixed-dose bictegravir, emtricitabine, and
adults with and without HIV infection, 2000-2016. JAMA Network Open 3 (6).
tenofovir alafenamide from boosted protease inhibitor-based regimens in
https://doi.org/10.1001/jamanetworkopen.2020.7954 e207954-e.
virologically suppressed adults with HIV-1: 48 week results of a randomised, open-

7
C.-H. Lu et al. Current Research in Pharmacology and Drug Discovery 2 (2021) 100044

Markham, A., 2018. Bictegravir: first global approval. Drugs 78 (5), 601–606. https:// non-inferiority trial. Lancet (Lond. Engl.) 390 (10107), 2073–2082. https://doi.org/
doi.org/10.1007/s40265-018-0896-4. Epub 2018/03/23. 10.1016/s0140-6736(17)32340-1. Epub 2017/09/05.
Masich, A., Badowski, M.E., Liedtke, M.D., Fulco, P.P., 2017. Evaluation of the concurrent Shah, B.M., Schafer, J.J., Priano, J., Squires, K.E., 2013. Cobicistat: a new boost for the
use of dolutegravir and metformin in human immunodeficiency virus-infected treatment of human immunodeficiency virus infection. Pharmacotherapy 33 (10),
patients. Int. J. STD AIDS 28 (12), 1229–1233. https://doi.org/10.1177/ 1107–1116. https://doi.org/10.1002/phar.1237. Epub 2013/03/09.
0956462417695995. Epub 2017/06/21. Snedecor, S.J., Radford, M., Kratochvil, D., Grove, R., Punekar, Y.S., 2019. Comparative
Masnoon, N., Shakib, S., Kalisch-Ellett, L., Caughey, G.E., 2017. What is polypharmacy? A efficacy and safety of dolutegravir relative to common core agents in treatment-naïve
systematic review of definitions. BMC Geriatr. 17 (1), 230. https://doi.org/10.1186/ patients infected with HIV-1: a systematic review and network meta-analysis. BMC
s12877-017-0621-2. Infect. Dis. 19 (1), 484. https://doi.org/10.1186/s12879-019-3975-6. Epub 2019/
Mathias, A.A., Hinkle, J., Shen, G., Enejosa, J., Piliero, P.J., Sekar, V., et al., 2008. Effect 05/31.
of ritonavir-boosted tipranavir or darunavir on the steady-state pharmacokinetics of Song, I., Borland, J., Chen, S., Patel, P., Wajima, T., Peppercorn, A., et al., 2012. Effect of
elvitegravir. JAIDS J. Acquired Immun. Defic. Syndr. 49 (2). food on the pharmacokinetics of the integrase inhibitor dolutegravir. Antimicrob.
May, M.T., Gompels, M., Delpech, V., Porter, K., Orkin, C., Kegg, S., et al., 2014. Impact Agents Chemother. 56 (3), 1627–1629. https://doi.org/10.1128/aac.05739-11. Epub
on life expectancy of HIV-1 positive individuals of CD4þ cell count and viral load 2011/12/21.
response to antiretroviral therapy. AIDS (Lond., Engl.) 28 (8), 1193–1202. https:// Song, I., Borland, J., Chen, S., Guta, P., Lou, Y., Wilfret, D., et al., 2014. Effects of enzyme
doi.org/10.1097/QAD.0000000000000243. inducers efavirenz and tipranavir/ritonavir on the pharmacokinetics of the HIV
Mehta, R., Piscitelli, J., Wolstenholme, A., Fu, C., Crauwels, H., Wynne, B., et al., 2020. integrase inhibitor dolutegravir. Eur. J. Clin. Pharmacol. 70 (10), 1173–1179.
The effect of moderate- and high-fat meals on the bioavailability of dolutegravir/ https://doi.org/10.1007/s00228-014-1732-8. Epub 2014/08/26.
rilpivirine fixed-dose combination tablet. Clin. Pharmacol. 12, 49–52. https:// Song, I., Borland, J., Arya, N., Wynne, B., Piscitelli, S., 2015. Pharmacokinetics of
doi.org/10.2147/CPAA.S250751. dolutegravir when administered with mineral supplements in healthy adult subjects.
Messiaen, P., Wensing, A.M., Fun, A., Nijhuis, M., Brusselaers, N., Vandekerckhove, L., J. Clin. Pharmacol. 55 (5), 490–496. https://doi.org/10.1002/jcph.439. Epub 2014/
2013. Clinical use of HIV integrase inhibitors: a systematic review and meta-analysis. 12/03.
PloS One 8 (1), e52562. https://doi.org/10.1371/journal.pone.0052562. Epub Song, I., Weller, S., Patel, J., Borland, J., Wynne, B., Choukour, M., et al., 2016a. Effect of
2013/01/24. carbamazepine on dolutegravir pharmacokinetics and dosing recommendation. Eur.
Naccarato, M., Yoong, D., Fong, I.W., 2017. Dolutegravir and metformin: a case of J. Clin. Pharmacol. 72 (6), 665–670. https://doi.org/10.1007/s00228-016-2020-6.
hyperlactatemia. AIDS 31 (15), 2176–2177. https://doi.org/10.1097/ Epub 2016/02/24.
qad.0000000000001617. Epub 2017/09/15. Song, I.H., Zong, J., Borland, J., Jerva, F., Wynne, B., Zamek-Gliszczynski, M.J., et al.,
Neely, M., Decosterd, L., Fayet, A., Lee, J.S., Margol, A., Kanani, M., et al., 2010. 2016b. The effect of dolutegravir on the pharmacokinetics of metformin in healthy
Pharmacokinetics and pharmacogenomics of once-daily raltegravir and atazanavir in subjects. J. Acquir. Immune Defic. Syndr. 72 (4), 400–407. https://doi.org/10.1097/
healthy volunteers. Antimicrob. Agents Chemother. 54 (11), 4619–4625. https:// qai.0000000000000983. Epub 2016/03/15.
doi.org/10.1128/AAC.00712-10. Epub 2010/09/09. Stribild® [package Insert], August 2020. Gilead Sciences, Inc., Foster City, CA.
Pandey, K.K., Grandgenett, D.P., 2008. HIV-1 integrase strand transfer inhibitors: novel Tivicay®[package Insert], June 2020. Viiv Healthcare, Research Triangle Park, NC.
insights into their mechanism of action. Epub 2009/11/17 Retrovirology (Auckl) 2, Triumeq®[package Insert], March 2020. Viiv Healthcare, Research Triangle Park, NC.
11–16. https://doi.org/10.4137/rrt.s1081. PubMed PMID: 19915684; PubMed Tsiang, M., Jones, G.S., Goldsmith, J., Mulato, A., Hansen, D., Kan, E., et al., 2016.
Central PMCID: PMCPMC2776739. Antiviral activity of bictegravir (GS-9883), a novel potent HIV-1 integrase strand
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of transfer inhibitor with an improved resistance profile. Antimicrob. Agents
Antiretroviral Agents in Adults and Adolescents with HIV, 2020 September 11. Chemother. 60 (12), 7086–7097. https://doi.org/10.1128/aac.01474-16. Epub
Department of Health and Human Services. http://aidsinfo.nih.gov/contentfiles/l 2016/09/21.
vguidelines/AdultandAdolescentGL.pdf. Wang, X., Cerrone, M., Ferretti, F., Castrillo, N., Maartens, G., McClure, M., et al., 2019.
Podany, A.T., Scarsi, K.K., Fletcher, C.V., 2017. Comparative clinical pharmacokinetics Pharmacokinetics of dolutegravir 100 mg once daily with rifampicin. Int. J.
and pharmacodynamics of HIV-1 integrase strand transfer inhibitors. Clin. Antimicrob. Agents 54 (2), 202–206. https://doi.org/10.1016/
Pharmacokinet. 56 (1), 25–40. https://doi.org/10.1007/s40262-016-0424-1. Epub j.ijantimicag.2019.04.009. Epub 2019/04/20.
2016/06/19. Wenning, L.A., Petry, A.S., Kost, J.T., Jin, B., Breidinger, S.A., DeLepeleire, I., et al.,
Powderly, W.G., 2010. Integrase inhibitors in the treatment of HIV-1 infection. 2009a. Pharmacokinetics of raltegravir in individuals with UGT1A1 polymorphisms.
J. Antimicrob. Chemother. 65 (12), 2485–2488. https://doi.org/10.1093/jac/ Clin. Pharmacol. Ther. 85 (6), 623–627. https://doi.org/10.1038/clpt.2009.12. Epub
dkq350. Epub 2010/09/21. 2009/03/13.
Ramanathan, S., Mathias, A.A., German, P., Kearney, B.P., 2011. Clinical pharmacokinetic Wenning, L.A., Hanley, W.D., Brainard, D.M., Petry, A.S., Ghosh, K., Jin, B., et al., 2009b.
and pharmacodynamic profile of the HIV integrase inhibitor elvitegravir. Clin. Effect of rifampin, a potent inducer of drug-metabolizing enzymes, on the
Pharmacokinet. 50 (4), 229–244. https://doi.org/10.2165/11584570-000000000- pharmacokinetics of raltegravir. Antimicrob. Agents Chemother. 53 (7), 2852–2856.
00000. Epub 2011/02/26. https://doi.org/10.1128/aac.01468-08. Epub 2009/05/13.
Ramanathan, S., Mathias, A., Wei, X., Shen, G., Koziara, J., Cheng, A., et al., 2013. World Health Organization, 2020 September. HIV/AIDS, 14. https://www.who.int/gh
Pharmacokinetics of once-daily boosted elvitegravir when administered in o/hiv/en/.
combination with acid-reducing agents, 1999 J. Acquir. Immune Defic. Syndr. 64 (1), Yamada, H., Ikushima, I., Nemoto, T., Ishikawa, T., Ninomiya, N., Irie, S., 2018. Effects of
45–50. https://doi.org/10.1097/QAI.0b013e31829ecd3b. Epub 2013/06/19. a nutritional protein-rich drink on the pharmacokinetics of elvitegravir, cobicistat,
Reese, M.J., Savina, P.M., Generaux, G.T., Tracey, H., Humphreys, J.E., Kanaoka, E., et al., emtricitabine, tenofovir alafenamide, and tenofovir compared with a standard meal
2013. In vitro investigations into the roles of drug transporters and metabolizing in healthy Japanese male subjects. Clin Pharmacol Drug Dev 7 (2), 132–142. https://
enzymes in the disposition and drug interactions of dolutegravir, a HIV integrase doi.org/10.1002/cpdd.365. Epub 2017/06/06.
inhibitor. Drug Metab. Dispos. 41 (2), 353–361. https://doi.org/10.1124/ Yonemura, T., Okada, N., Sagane, K., Okamiya, K., Ozaki, H., Iida, T., et al., 2018. Effects
dmd.112.048918. Epub 2012/11/08. of milk or apple juice ingestion on the pharmacokinetics of elvitegravir and cobicistat
Rock, A.E., DeMarais, P.L., Vergara-Rodriguez, P.T., Max, B.E., 2020. HIV-1 virologic in healthy Japanese male volunteers: a randomized, single-dose, three-way crossover
rebound due to coadministration of divalent cations and bictegravir. Infect. Dis. Ther. study. Clin Pharmacol Drug Dev 7 (7), 737–743. https://doi.org/10.1002/cpdd.425.
9 (3), 691–696. https://doi.org/10.1007/s40121-020-00307-4. Epub 2020/07/06. Epub 2018/01/25.
Saag, M.S., Gandhi, R.T., Hoy, J.F., Landovitz, R.J., Thompson, M.A., Sax, P.E., et al., Zeuli, J., Rizza, S., Bhatia, R., Temesgen, Z., 2019. Bictegravir, a novel integrase inhibitor
2020. Antiretroviral drugs for treatment and prevention of HIV infection in adults: for the treatment of HIV infection. Drugs Today (Barc) 55 (11), 669–682. https://
2020 recommendations of the international antiviral society-USA Panel. J. Am. Med. doi.org/10.1358/dot.2019.55.11.3068796. Epub 2019/12/17.
Assoc. 324 (16), 1651–1669. https://doi.org/10.1001/jama.2020.17025. Epub Zhang, H.C.J.W.X., Wang, H., Vu, A., Ling, J., Martin, H., et al., 2017. Clinical
2020/10/15. Pharmacology of the HIV Integrase Strand Transfer Inhibitor Bictegravir. Conference
Sax, P.E., Pozniak, A., Montes, M.L., Koenig, E., DeJesus, E., Stellbrink, H.J., et al., 2017. on Retroviruses and Opportunistic Infections. Feb 13-16. Seattle, WA).
Coformulated bictegravir, emtricitabine, and tenofovir alafenamide versus Zhu, L., Butterton, J., Persson, A., Stonier, M., Comisar, W., Panebianco, D., et al., 2010.
dolutegravir with emtricitabine and tenofovir alafenamide, for initial treatment of Pharmacokinetics and safety of twice-daily atazanavir 300 mg and raltegravir 400 mg
HIV-1 infection (GS-US-380-1490): a randomised, double-blind, multicentre, phase 3, in healthy individuals. Antivir. Ther. 15 (8), 1107–1114. https://doi.org/10.3851/
IMP1673. Epub 2010/12/15.