Ramanathan, Srinivasan PhD; Mathias, Anita PhD; Wei, Xuelian PhD; Shen, Gong PhD; Koziara, Joanna PhD; Cheng, Andrew MD, PhD; Kearney, Brian P. PharmD
Inhibitors of the HIV integrase enzyme responsible for integration of the viral DNA strand into the host cellular DNA represent a novel class of antiretrovirals (ARVs) targeting an essential process for viral replication. Elvitegravir is the first, once-daily strand transfer inhibitor approved for the treatment of HIV-1 infection as a component of the elvitegravir/cobicistat/emtricitabine/tenofovir DF single-tablet regimen (EVG/COBI/FTC/TDF STR; Stribild; Gilead Sciences, Foster City, CA). EVG/COBI/FTC/TDF STR demonstrated high rates of virologic efficacy and a favorable safety/tolerability profile in phase 3 studies in treatment-naive HIV-1–infected patients.1,2 Additionally, once-daily EVG was noninferior to twice-daily raltegravir in a phase 3 study in treatment-experienced HIV patients, when each was administered in combination with an active background regimen that included a ritonavir (RTV)-boosted protease inhibitor (PI/r).3
Elvitegravir is primarily metabolized by cytochrome P450 3A4 (CYP3A4) and secondarily by glucuronidation via uridine glucuronosyl transferase 1A1/3.4 Once-daily coadministration of EVG with either 100 mg of ritonavir (EVG/r; for EVG plus PI/r, RTV dose is that used to boost the PI) or 150 mg of cobicistat (EVG/co), both potent mechanism-based inhibitors of CYP3A4, results in a substantial increase in EVG plasma exposure. Mean elvitegravir trough concentration (Ctau or Ctrough), which is the best determinant of antiviral activity, is ∼10-fold above its in vitro protein binding adjusted 95% inhibitory concentration (IC95) following 150/100 mg of EVG/r administration.5,6
As a novel pharmacoenhancer, cobicistat has demonstrated similar ability as ritonavir to boost various CYP3A substrates other than EVG, such as the CYP3A probe midazolam, and HIV protease inhibitors atazanavir and darunavir.7–9
Acid-reducing agents (ARA), such as antacids, H2-receptor antagonists (H2RA; eg, famotidine), and proton pump inhibitors (PPIs; eg, omeprazole), are commonly used medications, including those receiving ARV treatment.10
In addition to the prevalence of ARA use by HIV-1–infected patients, the liability of reduced ARV drug exposure due to their physicochemical properties (eg, pH-dependent solubility in gastrointestinal tract) typically necessitates drug interaction assessment. Specifically for HIV-1 integrase inhibitors, due to their mechanism of action as an active site inhibitor that binds the integrase enzyme that chelates the divalent metal ions (Mg2+, Mn2+), drug interaction potential is high between the integrase inhibitor pharmacophore and the very high concentrations of divalent cations present in some antacids.11 The binding of the EVG pharmacophore to divalent cations causes potential to interact with higher concentrations of divalent cations, such as those observed in the local gastrointestinal tract with some antacids.
A series of 4 clinical studies evaluated the drug interaction between boosted EVG and ARA, including antacids with high concentrations of divalent and trivalent cations administered simultaneously or staggered by 2 or 4 hours. A broader effect of pH on EVG PK was also clinically evaluated to distinguish from mechanism of action-based drug interaction potential. The evaluations were primarily 1-way interactions, that is, effects of ARA on boosted EVG, given the lack of meaningful interactions/effects expected from boosted EVG on the ARA. This article presents a summary of key findings from these studies to inform upon the drug interaction between boosted EVG (thus, EVG/COBI/FTC/TDF single-tablet regimen) and ARA from 3 commonly used classes, a magnesium/aluminum-containing antacid, famotidine or omeprazole as representative H2-receptor antagonist, and PPI, respectively.
Subjects and Study Design
Phase 1, single-center, open-label, crossover (1-way interaction) studies in healthy male and female (nonpregnant, nonlactating) subjects were performed at MDS Pharma Services (Phoenix, AZ) (EVG/r drug interaction with antacid; Study 1), at Charles River Laboratories (formerly Northwest Kinetics, Inc) (Tacoma, WA) (EVG/r drug interaction with antacid or omeprazole; Study 2), or at SeaView Research, Inc (Miami, FL) (EVG/co drug interaction with famotidine or omeprazole; Studies 3 and 4).
Eligible subjects (aged, 18–45 years, inclusive) were administered the randomized study treatments as shown in Figure S1A for Studies 1 and 2 (see SDC, http://links.lww.com/QAI/A434) and Figure S1B for Studies 3 and 4 (see SDC, http://links.lww.com/QAI/A434). The study protocol and informed consent document were reviewed and approved by Independent Review Board (IRB) (Study 1: MDS Pharma Services IRB, Lincoln, NE; Study 2: Aspire IRB, La Mesa, CA; Studies 3 and 4: Independent IRB, Plantation, FL), and subjects provided written informed consent before study participation. Major inclusion criteria typically were healthy subjects based on medical history/physical examinations/laboratory evaluations, normal 12-lead electrocardiogram, normal renal function, creatinine clearance ≥80 mL/min, no evidence of HIV, hepatitis B virus (HBV) or hepatitis C virus infection, and use of at least 2 forms of contraception, including an effective barrier method. Exclusion criteria included plasma and blood donation within 7 and 56 days of study entry, respectively, active medical illness, use of prescription drugs within 28–30 days of study drug dosing (except vitamins, acetaminophen, ibuprofen, and/or hormonal contraceptive).
Study 1 entailed EVG/r administration alone or simultaneously with antacid, and Study 2 entailed administration of EVG/r alone, followed by staggered coadministration with antacid ±2 hours or ±4 hours, or coadministration with omeprazole (given 2 hours before due to fasted dosing requirement versus EVG/r dosing with food) as shown in Figure S1A (see SDC, http://links.lww.com/QAI/A434). Studies 3 and 4 entailed EVG/co dosing alone or in combination with famotidine or omeprazole (administered staggered by 12 hours or simultaneously) as shown in Figure S1B (see SDC, http://links.lww.com/QAI/A434). The duration of EVG/r or EVG/co dosing or that of the ARA was considered to be sufficient for PK (EVG) or pharmacodynamics steady state (ARA). Because EVG exposures are higher when taken with food, subjects received study drugs immediately after a standardized morning meal (roughly 400 kcal) with 240 mL (8 fluid ounces) of water. On the days of PK sampling, subjects fasted until after collection of the 4-hour postdose blood draw. Subjects were allowed to consume water as desired except 1 hour before and 2 hours after study drug dosing. Intensive PK sampling over 24 hours was performed in all studies.
EVG was supplied as 50 or 150 mg tablets, cobicistat as 150 mg tablets, ritonavir as 100 mg soft gelatin capsules, famotidine as 40 mg tablet, omeprazole as 20 or 40 mg capsule, and antacid was Maalox Max maximum strength over the counter liquid. Blood samples were collected in Vacutainer tubes containing anticoagulant (spray-dried dipotassium ethylenediaminetetraacetic acid) and inverted several times to mix the blood and the anticoagulant. Samples were kept on wet ice or refrigerated for ≤30 minutes and centrifuged for 10 minutes at 1200 relative centrifugal force (g-force) in a refrigerated centrifuge set at ∼4°C to harvest plasma.
EVG, RTV, and COBI plasma concentrations were determined using validated high-performance liquid chromatography/tandem mass spectrometry (HPLC/MS/MS) at Gilead Sciences, Inc (Durham, NC) or at Quest Pharma Services (Newark, DE) with previously reported bioanalytical methods.12,13 Additional details in brief are provided for Studies 3 and 4.
For EVG analysis, 50 μL of human plasma was spiked with deuterated internal standard (IS) and processed by solid phase extraction. The compounds were detected by MS/MS in the selected reaction monitoring mode using electrospray ionization with positive polarity, and the following ion transitions were monitored: m/z 448 → 344 and 456 → 344 for EVG and IS, respectively. The lower limit of quantitation for EVG was 20 ng/mL. For validation, inter-assay precision was less than 10% coefficient of variation and accuracy was within ±10%.
For COBI analysis, 50 μL of human plasma was spiked with a deuterated IS and then extracted using protein precipitation with methanol. The compounds were detected by MS/MS in the selected reaction monitoring mode using electrospray ionization with positive polarity, and the following ion transitions were monitored: m/z 776 → 606 and 784 → 614 for COBI and IS, respectively. The lower limit of quantitation for COBI was 5 ng/mL. For validation, interassay precision was less than 10% coefficient of variation and accuracy was within ±10%.
PK parameters of EVG, COBI, and RTV were estimated by application of a nonlinear curve-fitting software package (WinNonlin software, Professional Edition; Pharsight Corporation, Mountain View, CA) using noncompartmental methods and included maximum observed plasma concentration (Cmax), time to reach maximum concentration (Tmax), area under the concentration–time curve over the dosing interval (AUCtau, calculated using the linear up-log down trapezoidal method; 0–24 hours for all 3 analytes), elimination half-life (T1/2), and concentration at the end of dosing interval (Ctau).
A parametric (normal theory) analysis of variance using a mixed effects model appropriate for a crossover design was fit to the natural logarithmic transformation of AUCtau, Cmax, and Ctau of EVG and COBI. Sample size of the study was based on variability estimates of Cmax, AUCtau, and Ctau for the analytes and accounted for potential dropouts. The final sample size provided at least 90% power to conclude lack of PK alteration based on the expected ratio of geometric least squares means of treatments (coadministered:alone) of 100% and associated 90% confidence interval (CI) range of 70% to 143% for all 3 analytes. The fixed and random effects were study treatment and subject, respectively.
The 90% CI boundaries for lack of PK alteration of EVG (70% to 143%) were chosen based on the efficacy of EVG/r in a phase 2 study that evaluated multiple EVG doses (125, 50, and 20 mg) and the cumulative safety data at the 125 mg dose and higher doses evaluated in phase 1 studies. The 150 mg dose of EVG (phase 3 formulation which is equivalent to 125 mg dose of phase 2 formulation) has been shown to be efficacious and well tolerated in phase 3 studies in treatment-naive (boosted with cobicistat as Stribild) and treatment-experienced (in combination with ritonavir-boosted protease inhibitors) in HIV-1 patients.
The PK of COBI was evaluated using exploratory 90% CI boundaries of 70% to 143% chosen based on the overall range of observed COBI exposures that provide robust CYP3A inhibition. Subjects with an evaluable PK profile for the coadministered:alone treatment pair were included in the PK analysis.
The demographic characteristics of the subjects enrolled in Studies 1 through 4 are provided in Table S1 (see SDC, http://links.lww.com/QAI/A434). There was no discontinuation in Study 1 that evaluated EVG/r plus antacid interaction cohort or in Study 4. In Study 2, subject discontinuations were primarily due to safety/tolerability, protocol violation, and withdrawn consent (4, 4, and 2, respectively). In Study 3, 1 subject discontinued before study completion due to pregnancy, which was disallowed on-study.
In all 4 studies, treatment-emergent adverse events (AEs) were generally mild to moderate, with no serious AEs, grade 3 or 4 AEs or deaths observed. Most graded laboratory abnormalities were mild to moderate in severity. The types of AEs observed in these studies were consistent with those previously observed in other EVG and/or COBI studies.1–3,6–9
In Study 1, treatment-emergent AEs were observed in 5 (38.5%) of 13 subjects, which were generally gastrointestinal system disorders (diarrhea and flatulence). In Study 2, most AEs occurred during administration of EVG/r, with most commonly reported AEs being headache (17%), nausea (5%), and diarrhea (5%). In Study 3, incidence of AEs were 9%–27% across treatments (EVG/co administration alone or in combination with famotidine or omeprazole), including gastrointestinal system disorders (dyspepsia). In Study 4, 31%–44% of subjects experienced treatment emergent AEs, with the most common AE reported being headache.
The plasma concentration–time profiles of EVG after administration of multiple EVG/r doses alone and in combination with ARA are presented in Figures 1A–C. Corresponding EVG PK parameters are presented in Table S2A and Table S2B (see SDC, http://links.lww.com/QAI/A434). Peak EVG concentrations were observed ∼4 hours following dosing alone or with ARA across studies. EVG T1/2 was similar across treatments (9.4–11.8 hours). The percentage of geometric least squares means (90% CI) for EVG plasma Cmax, AUCtau, and Ctau were contained within the predefined lack of PK alteration bounds in all cases except for simultaneous coadministration with antacid in Study 1, where they were below these bounds.
Plasma concentration data for EVG/co administration ± omeprazole or famotidine are shown in Figure 2B (omeprazole) and Figure 3B (famotidine), and the EVG PK parameters are presented in Table 1 and Table S2B (see SDC, http://links.lww.com/QAI/A434). EVG PK were comparable following EVG/co administration alone or in the presence of omeprazole/famotidine and the exposure parameters were within the predefined lack of PK alteration bounds. These data indicate no clinically relevant changes in EVG PK upon coadministration with omeprazole or famotidine or upon staggered coadministration with antacid (at least 2 hours).
The plasma concentration–time profiles of COBI following multiple dose administration as EVG/co alone or in combination with ARA are presented in Figures 2A, 3A. COBI PK parameters are presented in Table 1, Table 2, and Table S2B (see SDC, http://links.lww.com/QAI/A434). The percentage of geometric least squares means for COBI plasma Cmax, AUCtau, and Ctau were contained within the lack of PK predefined alteration bounds of 70%–143% in all cases, indicating the lack of meaningful alteration in its PK upon coadminstration with famotidine or omeprazole.
A series of multiple-dose crossover studies systematically performed characterized the potential drug interactions between boosted EVG and famotidine or omeprazole. In 2 studies with EVG/r, simultaneous dosing with antacids containing high concentrations of divalent cations was shown to reduce EVG exposures (Study 1), whereas a follow-up study demonstrated a staggered dosing approach (at least 2 hours before or after antacid administration) that offset the interaction (Study 2). The study also showed the reduction in EVG exposure with antacid to be a likely local gastrointestinal complexation phenomenon rather than a broader pH effect.
Based on a modest pH dependence of COBI solubility, 2 subsequent studies evaluated potential changes in COBI, and consequently EVG, exposures upon coadministration with famotidine initially in a staggered (12 hours) fashion (Study 3), followed by simultaneous coadministration (Study 4). Study 3 also evaluated the potential for EVG/co interaction with omeprazole. These studies indicated no effect of H2RA or PPIs on EVG or COBI PK. Collectively, these data indicate no clinically relevant changes in EVG and COBI PK, either as individual agents or as EVG/COBI/FTC/TDF STR (based on lack of pH effect on FTC or tenofovir PK), due to changes in gastric pH. Coadministration of boosted-EVG and ARAs was generally well tolerated across all studies, with AEs mostly being mild to moderate.
In evaluating PPIs, gastric pH-based effects were considered the main driver for the potential for interaction with boosted EVG, and a metabolic interaction was deemed unlikely, due to the nonoverlapping metabolic pathways/profiles of omeprazole and EVG/co. Omeprazole is a weak inducer of CYP1A2 and a moderate inhibitor of CYP2C19, neither enzyme being involved in the metabolism of EVG or COBI.
The observed changes in EVG PK with antacids are consistent with its pharmacodynamic mechanism of action and with interactions between antacids and with other HIV integrase inhibitors, including raltegravir and dolutegravir.14,15 Raltegravir exposures (C12 hr) were 67% lower, whereas dolutegravir plasma exposures (AUC, Cmax) were up to 74% lower upon simultaneous coadministration with an aluminium/magnesium-containing antacid. A suitable dose modification to offset the observed interaction has not been provided for raltegravir; dolutegravir should be administered 2 hours before or 6 hours after antacid. Dolutegravir exposures are also lower by up to 35% with multivitamins. For boosted EVG, the observed interaction upon simultaneous antacid coadministration represents the potential for maximum interaction (worst case scenario), and staggered dosing by at least 2 hours is recommended based on the lack of EVG exposure differences with 2 or 4 hours stagger. Further evaluation of the potential influence of the relative amounts of cations in other co-medications, such as nutritional supplements, on Stribild efficacy was also performed. In the phase 2 and 3 studies with Stribild, the antiviral efficacy was comparable with multivitamin use (91% patients with HIV RNA <50 copies/mL using Food and Drug Administration–defined Snapshot analysis) versus nonuse (88%), indicating the lack of clinically relevant influence of these agents on EVG PK. The utility of these data are somewhat limited, however, by the absence of information of the relative timing of administration of these agents. Antacid coadministration is not considered to impact COBI exposures based on physicochemical or pH considerations.
The broader effect of pH on other integrase inhibitors varied, with no clinically relevant changes in dolutegravir PK, but raltegravir Cmax and AUCinf being 3- to 4-fold higher upon coadministration with omeprazole and attributed to higher solubility at increased gastric pH.16
Given both the prevalence of use among HIV-1–infected patients and the physicochemical considerations, evaluation of drug interactions between ARVs and ARA is essential. A noteworthy interaction is that between atazanavir and famotidine or omeprazole.17 Based on its inverse pH solubility profile, atazanavir exposures are drastically lower with these agents and strict dosing recommendations have been developed through several drug interaction studies. In contrast, the no clinically relevant changes were observed in the PK of other HIV protease inhibitors, such as darunavir, lopinavir, and fosamprenavir, when administered with omeprazole.18–20
The results of the present studies provide a clear dosing guidance for the use of boosted EVG, regardless of booster (ie, RTV or COBI) or use as individual agent or EVG/COBI/FTC/TDF single-tablet regimen, and ARAs. No dose modification of Stribild (in treatment-naive patients) or RTV-boosted EVG (in treatment-experienced population) is needed upon coadministration with H2RA or PPI.
In conclusion, coadministration of boosted-EVG or Stribild with ARA such as H2-receptor antagonists or PPIs or with multivitamins does not warrant dose modification; a 2-hour stagger is recommended when coadministered with antacids.
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