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This study investigates the impact of severe renal impairment on the pharmacokinetics of cabotegravir, an investigational HIV‐1 integrase inhibitor. This was a phase I, open‐label, parallel‐group, multicenter study conducted in 8 participants with severe renal impairment (creatinine clearance 90 mL/min; 2 women/group; 6 men/group) matched for sex, age (±10 years), and body mass index (±25%). Participants received a single 30‐mg oral cabotegravir tablet to determine total and unbound plasma cabotegravir concentrations. Arithmetic and geometric least squares means were calculated, and cabotegravir noncompartmental pharmacokinetic parameters were compared using geometric least squares mean ratios with 90% confidence intervals. Safety was assessed throughout the study. Geometric least squares mean ratios (90% confidence intervals) were 0.97 (0.84–1.14) for area under the plasma concentration‐time curve extrapolated to infinity, 1.01 (0.87–1.17) for maximum observed plasma concentration, 1.31 (0.84–2.03) for unbound cabotegravir 2 hours after dosing, and 1.51 (1.19–1.92) for unbound cabotegravir 24 hours after dosing. All adverse events were grade 1, except grade 3 lipase elevation in a participant with renal impairment. Severe renal impairment did not impact plasma cabotegravir exposure, and cabotegravir may be administered without dose adjustment in renal impairment among patients not receiving renal replacement.

Cabotegravir is an investigational integrase inhibitor in development for the treatment and pre‐exposure prophylaxis of HIV‐1 infection. Liver disease is a major cause of morbidity and mortality in HIV‐infected individuals and can impact the pharmacokinetics (PK) of HIV medications. This phase 1 study evaluated the PK of cabotegravir in individuals with moderate hepatic impairment (n = 8) versus healthy controls (n = 8). Participants received a single oral cabotegravir 30‐mg tablet and underwent PK sampling to determine total and unbound plasma cabotegravir concentrations. Calculated geometric least‐squares mean ratios (90% confidence intervals) for individuals with hepatic impairment versus healthy controls were 0.73 (0.50‐1.06) for AUC0‐∞, 0.69 (0.51‐0.93) for Cmax, 1.40 (0.80‐2.46) for unbound concentration (CU) 2 hours postdose, 1.55 (0.82‐2.94) for CU at 24 hours, 2.14 (1.57‐2.90) for unbound fraction (FU) at 2 hours, and 1.90 (1.14‐3.18) for FU at 24 hours. Adverse events (AEs) occurred in 2 individuals with hepatic impairment and 3 healthy controls and were grade 1/2 in severity. No participant discontinued because of AEs. Increased FU resulted in a modest decrease in total plasma exposure not considered clinically relevant. We conclude that cabotegravir may be administered without dose adjustment in patients with mild to moderate hepatic impairment.

Aims This study aimed to investigate whether cabotegravir (CAB), an integrase inhibitor in development for treatment and prevention of human immunodeficiency virus-1, influences the pharmacokinetics (PK) of a levonorgestrel (LNG) and ethinyl oestradiol (EO)–containing oral contraceptive (OC) in healthy women. Methods In this open-label, fixed-sequence crossover study, healthy female subjects received LNG 0.15 mg/EO 0.03 mg tablet once daily Days 1–10 alone and with oral CAB 30 mg once daily Days 11–21. At the end of each treatment period, subjects underwent predose sampling for concentrations of follicle-stimulating hormone, luteinizing hormone, and progesterone and serial PK sampling for plasma LNG, EO, and CAB concentrations. Results Twenty women were enrolled, and 19 completed the study. One subject was withdrawn due to an adverse event unrelated to study medications. Geometric least squares mean ratios (90% confidence interval) of LNG + CAB vs. LNG alone for LNG area under the plasma concentration–time curve over the dosing interval of duration τ and maximum observed plasma concentration were 1.12 (1.07–1.18) and 1.05 (0.96–1.15), respectively. Geometric least squares mean ratio (90% confidence interval) of EO + CAB vs. EO alone for EO area under the plasma concentration–time curve over the dosing interval of duration τ and maximum observed plasma concentration were 1.02 (0.97–1.08) and 0.92 (0.83–1.03), respectively. Steady-state CAB PK parameters were comparable to historical values. There was no apparent difference in mean luteinizing hormone, follicle-stimulating hormone, and progesterone concentrations between periods. No clinically significant trends in laboratory values, vital signs, or electrocardiography values were observed. Conclusions Repeat doses of oral CAB had no significant effect on LNG/EO PK or pharmacodynamics, which supports CAB coadministration with LNG/EO OCs in clinical practice.

The goal of this study was to explore the relationships between tenofovir (TFV) and emtricitabine (FTC) disposition and markers of biologic aging, such as the frailty phenotype and p16INK4a gene expression. Chronologic age is often explored in population pharmacokinetic (PK) analyses, and can be uninformative in capturing the impact of aging on physiology, particularly in human immunodeficiency virus (HIV)-infected patients. Ninety-one HIV-infected participants provided samples to quantify plasma concentrations of TFV/FTC, as well as peripheral blood mononuclear cell (PBMC) samples for intracellular metabolite concentrations; 12 participants provided 11 samples, and 79 participants provided 4 samples, over a dosing interval. Nonlinear mixed effects modeling of TFV/FTC and their metabolites suggests a relationship between TFV/FTC metabolite clearance (CL) from PBMCs and the expression of p16INK4a , a marker of cellular senescence. This novel approach to quantifying the influence of aging on PKs provides rationale for further work investigating the relationships between senescence and nucleoside phosphorylation and transport.

Unbound drug is the pharmacodynamically relevant concentration. This study aimed to determine if chronologic age or markers of biologic aging, such as the frailty phenotype and p16INK4a gene expression, altered unbound pharmacokinetics (PKs) of efavirenz (EFV) and atazanavir/ritonavir (ATV/RTV). Sixty human immunodeficiency virus (HIV)-infected participants receiving EFV and 31 receiving ATV/RTV provided 1 to 11 samples to quantify total and unbound plasma concentrations. Population PK models with total and unbound concentrations simultaneously described are developed for each drug. The unbound fractions for EFV, ATV, and RTV are 0.65%, 5.67%, and 0.63%, respectively. Covariate analysis suggests RTV unbound PK is sensitive to body size; unbound fraction of RTV is 34% lower with body mass index (BMI) above 30 kg/m2 . No alterations in drug clearance or unbound fraction with age, frailty, or p16INK4a expression were observed. Assessing functional and physiologic aging markers to inform potential PK changes is necessary to determine if drug/dosing changes are warranted in the aging population.

Background HIV may amplify immunological, physiological and functional changes of ageing. We determined associations of frailty phenotype, a T-cell senescence marker (p16INK4a expression), age and demographics with exposures of the intracellular metabolites (IM) and endogenous nucleotides (EN) of tenofovir/emtricitabine (TFV/FTC), efavirenz (EFV), atazanavir (ATV) and ritonavir (RTV). Methods Plasma and peripheral blood mononuclear cell samples for drug, IM and EN concentrations were collected at four time points in HIV+ adults receiving TFV/FTC with EFV or ATV/RTV. Subjects underwent frailty phenotyping and p16INK4a expression analysis. Non-compartmental analysis generated an area under the curve (AUC) for each analyte. Spearman rank correlation and Kruskal–Wallis tests were used to assess associations between AUC, demographics and ageing markers, adjusting for multiple comparisons with the Holm procedure. Results Subjects ( n=79) ranged in age from 22–73 years (median 48 years); 48 were African-American, 24 were female, 54 received EFV. Three subjects (range 51–60 years) demonstrated frailty, with 17 subjects (range 26–60 years) demonstrating pre-frailty. Negative associations were observed between p16INK4a expression and each of FTC-triphosphate (r=-0.45), deoxyadenosine triphosphate (dATP; r=-0.47) and deoxycytidine triphosphate (dCTP; r=-0.57) AUCs ( P-values ≤0.02). TFV and FTC AUCs were larger among subjects with lower renal function or higher chronological age ( P-values ≤0.05). No associations were observed for EFV, ATV or RTV AUCs. Conclusions Associations of IM/EN exposure and p16INK4a expression observed here suggest that senescence may alter drug phosphorylation, metabolism or transport. This finding warrants further mechanistic study to ensure optimal treatment in the ageing HIV+ population. Clinicaltrials.gov NCT01180075.

Drug-drug interactions between antiretroviral medications and rifampin complicate the treatment of HIV and tuberculosis coinfection. This study evaluated the effect of rifampin on the pharmacokinetics of oral cabotegravir, an integrase strand transfer inhibitor being investigated for long-acting treatment and prevention of HIV-1 infection. This was a phase I, single-center, open-label, fixed-sequence crossover study in healthy adults. The objective was to evaluate the effect of steady-state rifampin on the single-dose plasma pharmacokinetics of cabotegravir. Subjects received a single oral dose of cabotegravir (30 mg) on day 1 followed by plasma sampling on days 1 to 8. Treatment with once-daily oral rifampin (600 mg) occurred on days 8 to 28. Subjects received a second dose of 30 mg cabotegravir on day 21 followed by pharmacokinetic sampling on days 21 to 28. Fifteen subjects were enrolled and completed the study. Rifampin decreased the cabotegravir area under the concentration-time curve from 0 h to infinity and the half-life by 59% and 57%, respectively, whereas oral clearance was increased 2.4-fold. The maximum concentration of cabotegravir in plasma was unaffected by coadministration with rifampin. All adverse events were mild in severity, with chromaturia attributed to rifampin observed in all subjects. Rifampin induction of cabotegravir metabolism resulted in increased cabotegravir oral clearance and significantly decreased cabotegravir exposures. Rifampin is expected to increase cabotegravir clearance following long-acting injectable administration. Concomitant administration of rifampin with oral and long-acting formulations of cabotegravir is not recommended currently without further study. (This study has been registered at ClinicalTrials.gov under registration no. NCT02411435.)

Objectives As the HIV-infected population ages, the role of cellular senescence and inflammation on co-morbid conditions and pharmacotherapy is increasingly of interest. p16INK4a expression, a marker for aging and senescence in T-cells, is associated with lower intracellular concentrations of endogenous nucleotides (EN) and nucleos(t)ide reverse transcriptase inhibitors (NRTIs). This study expands on these findings by determining whether inflammation is contributing to the association of p16INK4a expression with intracellular metabolite (IM) exposure and endogenous nucleotide concentrations. Methods Samples from 73 HIV-infected adults receiving daily tenofovir/emtricitabine (TFV/FTC) with either efavirenz (EFV) or atazanavir/ritonavir (ATV/r) were tested for p16INK4a expression, and plasma cytokine and intracellular drug concentrations. Associations between p16INK4a expression and cytokine concentrations were assessed using maximum likelihood methods, and elastic net regression was applied to assess whether cytokines were predictive of intracellular metabolite/endogenous nucleotide exposures. Results Enrolled participants had a median age of 48 years (range 23-73). There were no significant associations between p16INK4a expression and cytokines. Results of the elastic net regression showed weak relationships between IL-1Ra and FTC-triphosphate and deoxyadenosine triphosphate exposures, and MIP-1β, age and TFV-diphosphate exposures. Conclusions In this clinical evaluation, we found no relationships between p16INK4a expression and cytokines, or cytokines and intracellular nucleotide concentrations. While inflammation is known to play a role in this population, it is not a major contributor to the p16INK4a association with decreased IM/EN exposures in these HIV-infected participants.

Aims This study aimed to investigate whether cabotegravir (CAB), an integrase inhibitor in development for treatment and prevention of human immunodeficiency virus‐1, influences the pharmacokinetics (PK) of a levonorgestrel (LNG) and ethinyl oestradiol (EO)–containing oral contraceptive (OC) in healthy women. Methods In this open‐label, fixed‐sequence crossover study, healthy female subjects received LNG 0.15 mg/EO 0.03 mg tablet once daily Days 1–10 alone and with oral CAB 30 mg once daily Days 11–21. At the end of each treatment period, subjects underwent predose sampling for concentrations of follicle‐stimulating hormone, luteinizing hormone, and progesterone and serial PK sampling for plasma LNG, EO, and CAB concentrations. Results Twenty women were enrolled, and 19 completed the study. One subject was withdrawn due to an adverse event unrelated to study medications. Geometric least squares mean ratios (90% confidence interval) of LNG + CAB vs. LNG alone for LNG area under the plasma concentration–time curve over the dosing interval of duration τ and maximum observed plasma concentration were 1.12 (1.07–1.18) and 1.05 (0.96–1.15), respectively. Geometric least squares mean ratio (90% confidence interval) of EO + CAB vs. EO alone for EO area under the plasma concentration–time curve over the dosing interval of duration τ and maximum observed plasma concentration were 1.02 (0.97–1.08) and 0.92 (0.83–1.03), respectively. Steady‐state CAB PK parameters were comparable to historical values. There was no apparent difference in mean luteinizing hormone, follicle‐stimulating hormone, and progesterone concentrations between periods. No clinically significant trends in laboratory values, vital signs, or electrocardiography values were observed. Conclusions Repeat doses of oral CAB had no significant effect on LNG/EO PK or pharmacodynamics, which supports CAB coadministration with LNG/EO OCs in clinical practice.

Purpose of review Long-acting cabotegravir may provide a novel therapeutic option for both the treatment and prevention of HIV-1 infection that does not necessitate adherence to a daily regimen. The present review will highlight the unique formulation properties and pharmacologic attributes of long-acting cabotegravir nanosuspension. Recent findings Cabotegravir is a potent integrase strand transfer inhibitor that has been formulated as an oral tablet for daily administration and as a long-acting injectable nanosuspension. Long-acting cabotegravir is readily absorbed following intramuscular and subcutaneous administration and has an elimination half-life of approximately 40 days, allowing for administration on a monthly or less frequent schedule. Repeat-dose pharmacokinetic studies and population pharmacokinetic modeling indicate monthly and bi-monthly dosing achieves clinically relevant plasma concentrations considered effective for HIV maintenance therapy and that quarterly injections are appropriate for investigation as preexposure prophylaxis. Cabotegravir is primarily metabolized by uridine diphosphate glucuronosyltransferase 1A1 and is unlikely to be impacted by the cytochrome P450 metabolic pathway. In vitro and in vivo data suggest cabotegravir has a low propensity to cause, or be subject to, significant drug interactions. Summary The pharmacologic profile of long-acting cabotegravir supports its continued development for both treatment and prevention of HIV-1 infection.

Background Cabotegravir (CAB) is an integrase inhibitor in phase 3 clinical trials for the treatment and prevention of HIV. CAB undergoes glucuronidation via UGT1A1 with Methods This was a multi-center, single-dose study of oral CAB 30mg administered to subjects with severe renal impairment (creatinine clearance [CLcr] Results Sixteen subjects completed study; 12 (75%) male, mean age 54 years (range:35–69), mean BMI 28 kg/m2 (range: 24–35), and mean CLcr 22 mL/minute (range: 17–29) and 121 mL/minute (range: 95–162) for renal impaired and healthy subjects, respectively. CAB PK parameters were similar between severe renal impairment and healthy subjects. Based on preliminary PK, GLS mean ratios (90% CI) for AUC(0-¥), Cmax, C24, CL/F, and t1/2 were 0.97 (0.835, 1.14), 1.01 (0.865, 1.17), 1.02 (0.868, 1.20), 1.03 (0.881, 1.20) and 0.93 (0.831, 1.04), respectively. Although highly protein bound, the unbound fraction was higher in subjects with severe renal impairment with GLS mean ratio (90%CI) of 1.31 (0.843, 2.03) at 2 hours and 1.51 (1.19, 1.92) at 24 hours post dose. One renal impairment subject developed grade 3 lipase elevation considered drug-related by investigator, otherwise all reported adverse events (AE) were Grade 1 in severity with no serious AEs reported. Conclusion Plasma CAB exposures in subjects with severe renal impairment were similar to healthy subjects; therefore, no dose adjustment of CAB is required in renal impairment. Although no data are available, CAB PK is not expected to be affected in subjects undergoing dialysis given CAB’s non-renal clearance and high plasma protein binding (~99%). Disclosures R. Parasrampuria, GlaxoSmithKline: Employee and Shareholder, Salary; S. Ford, PAREXEL International: Employee, Salary; Y. Lou, PAREXEL International: Employee, Salary; C. Fu, PAREXEL International: Employee, Salary; K. Bakshi, GlaxoSmithKline: Employee and Shareholder, Salary; A. Tenorio, ViiV Healthcare: Employee and Shareholder, Salary; C. Trezza, ViiV Healthcare: Employee and Shareholder, Salary; W. Spreen, ViiV Healthcare: Employee and Shareholder, Salary; P. Patel, ViiV Healthcare: Employee and Shareholder, Salary

Background Cabotegravir (CAB) is an integrase inhibitor in phase 3 clinical trials for the treatment and prevention of HIV. CAB undergoes hepatic metabolism primarily via UGT1A1; thus hepatic impairment has the potential to affect CAB exposure. Methods This was a multi-center, single-dose, open-label, parallel group study to evaluate the effect of moderate hepatic impairment on the pharmacokinetics (PK) and safety of CAB. Adults with moderate hepatic impairment as determined by Child-Pugh classification score of 7–9 (n = 8) and matched healthy control subjects (n = 8) were enrolled. Control subjects were matched for gender, age (±10 years), and body mass index (BMI) (±25%). Subjects received oral CAB 30 mg as a single dose in the fasted state followed by serial PK sampling for 168 hours. CAB unbound concentrations at 2 and 24 hours after dosing were determined by equilibrium dialysis. Non-compartmental PK analysis was performed; geometric least squares (GLS) mean ratios (hepatic impaired group/control group) and 90% confidence intervals (CI) were generated. Results Sixteen subjects completed study; 12 (75%) male, mean age 59 years (range: 51–67), mean BMI 29 kg/m2 (range: 21–37), and total Child Pugh score in range of 7–9. CAB PK parameters were similar between subjects with moderate hepatic impairment and matched healthy subjects. The GLS mean ratios (90% CI) for AUC(0-∞), Cmax, C24, CL/F, and t1/2 were 0.73 (0.50, 1.06), 0.69 (0.51, 0.93), 0.73 (0.53, 1.02), 1.38 (0.95, 2.01), and 0.82 (0.65, 1.04), respectively. Although highly protein bound, the unbound fraction of CAB was increased in subjects with moderate hepatic impairment relative to healthy subjects with GLS mean ratio (90%CI) of 2.14 (1.57, 2.90) at 2 hours post dose and 1.90 (1.14, 3.18) at 24 hours post dose; this was associated with lower serum albumin concentrations and was not considered clinically significant. All adverse events (AE) were reported as mild (Grade 1) to moderate (Grade 2) in severity and no serious AEs were reported. Conclusion Plasma exposures of CAB in subjects with moderate hepatic impairment were similar to those in healthy subjects. No dose adjustment of CAB is required for subjects with mild to moderate hepatic impairment. Disclosures J. S. Shaik, GlaxoSmithKline: Employee and Shareholder, Salary; S. Ford, PAREXEL International: Employee, Salary; Y. Lou, PAREXEL International: Employee, Salary; Z. Zhang, PAREXEL International: Employee, Salary; K. Bakshi, GlaxoSmithKline: Employee and Shareholder, Salary; A. Tenorio, ViiV Healthcare: Employee and Shareholder, Salary; C. Trezza, ViiV Healthcare: Employee and Shareholder, Salary; W. Spreen, ViiV Healthcare: Employee and Shareholder, Salary; P. Patel, ViiV Healthcare: Employee and Shareholder, Salary

The incidence of HIV remains alarmingly high in many parts of the world. Prophylactic use of antiretrovirals, capable of concentrating in the anatomical sites of transmission, may reduce the risk of infection after an unprotected sexual exposure. To date, orally and topically administered antiretrovirals have exhibited variable success in preventing HIV transmission in large-scale clinical trials. Antiretroviral mucosal pharmacokinetics may help explain the outcomes of these investigations. Penetration and accumulation of antiretrovirals into sites of transmission can influence dosing strategies and pre-exposure prophylaxis clinical trial design. Antiretroviral tissue distribution varies widely within and between drug classes, attributed in part to their physicochemical properties and tissue-specific drug transporter expression. Nucleoside (-tide) reverse transcriptase inhibitors, the CCR5 antagonist maraviroc, and the integrase inhibitor raltegravir demonstrate the highest penetration into the male and female reproductive tracts and colorectal tissue relative to blood. This review will describe antiretroviral exposure in anatomic sites of transmission, and place these findings in context with the prevention of HIV and the efficacy of pre-exposure prophylactic strategies.