Polina German

Effect of cobicistat on glomerular filtration rate in subjects with normal and impaired renal function.

Objective:This study evaluated the effect of cobicistat (COBI) on glomerular filtration rate in subjects with normal renal function (RF) or with mild/moderate renal impairment, by comparing creatinine clearance [estimated glomerular filtration rate (eGFR)] with actual GFR (aGFR) using iohexol, a probe drug excreted by glomerular filtration. COBI is a potent CYP3A inhibitor (pharmacoenhancer) currently in phase 3 testing with elvitegravir, atazanavir, and darunavir. Methods:Normal RF subjects received COBI 150 mg QD, ritonavir (RTV) 100 mg QD, or placebo for 7 days; subjects with mild/moderate renal impairment received COBI 150 mg QD. The eGFR and aGFR were measured on days 0, 7, and 14 and within-subject changes calculated relative to day 0. COBI and RTV pharmacokinetics were analyzed on day 7. Results:All 36 subjects in cohort 1 and 17 of 18 subjects in cohort 2 completed all study treatments. Study treatments were well tolerated. Small increases in serum creatinine with corresponding mean decreases in eGFR (∼10 mL/min or mL/min per 1.73 m2) were observed on day 7 relative to day 0 in subjects receiving COBI (P < 0.05). The decreases were reversible on COBI discontinuation; mean eGFR values returned to baseline on day 14 (P > 0.05). No statistically significant changes in aGFR on days 7 or 14 relative to day 0 were seen with COBI (P > 0.05). No statistically significant decreases in aGFR or eGFR were observed with RTV or placebo. Conclusions:COBI affects eGFR but not the actual GFR. The time to onset, magnitude, and time to resolution of changes in eGFR are consistent with altered proximal tubular secretion of creatinine through inhibition of drug transporters.

Clinical Pharmacokinetic and Pharmacodynamic Profile of the HIV Integrase Inhibitor Elvitegravir

Elvitegravir is a potent, boosted, once-daily, HIV integrase inhibitor with antiviral activity against wild-type and drug-resistant strains of HIV. Because elvitegravir is metabolized primarily by cytochrome P450 (CYP) 3A enzymes, coadministration with a strong CYP3A inhibitor such as ritonavir or cobicistat (also known as GS-9350), an investigational pharmacoenhancer, substantially increases (boosts) elvitegravir plasma exposures and prolongs its elimination half-life to ∼9.5 hours, allowing once-daily administration of a low 150 mg dose. Boosting also results in low intra- and intersubject pharmacokinetic variability and high elvitegravir trough concentrations (∼6- to 10-fold above the concentration producing 95% inhibition of wild-type HIV-1 virus [IC95] of 45 ng/mL [protein binding-adjusted]), which is the pharmacokinetic parameter best associated with its antiviral activity.Data from extensive evaluation of the potential for boosted elvitegravir to undergo drug-drug interactions with other antiretroviral agents or concomitant medications indicate the absence of clinically relevant interactions or the need for dose modification in several cases, except for dose reduction of elvitegravir from 150 to 85 mg when coadministered with atazanavir/ritonavir or lopinavir/ritonavir. Dose adjustments for maraviroc and rifabutin, when each is coadministered with boosted elvitegravir, are consistent with their observed interactions with other ritonavir-boosted agents. The presence of a strong CYP3A inhibitor such as ritonavir or cobicistat renders the potential for increase in systemic exposures of CYP3A substrates coadministered with boosted elvitegravir. This article reviews a comprehensive pharmacology programme, including drug-drug interaction studies, mechanistic and special population studies, that has allowed a thorough understanding of elvitegravir clinical pharmacokinetics and its impact on pharmacodynamics.

Clinical Pharmacology of Artemisinin-Based Combination Therapies

Malaria, a disease transmitted by the female Anopheles mosquito, has had devastating effects on human populations for more than 4000 years. Treatment of the disease with single drugs, such as chloroquine, sulfadoxine/pyrimethamine or mefloquine, has led to the emergence of resistant Plasmodium falciparum parasites that lead to the most severe form of the illness. Artemisinin-based combination therapies are currently recommended by WHO for the treatment of uncomplicated P. falciparum malaria. Artemisinin and semisynthetic derivatives, including artesunate, artemether and dihydroartemisinin, are short-acting antimalarial agents that kill parasites more rapidly than conventional antimalarials, and are active against both the sexual and asexual stages of the parasite cycle. Artemisinin fever clearance time is shortened to 32 hours as compared with 2–3 days with older agents. To delay or prevent emergence of resistance, artemisinins are combined with one of several longer-acting drugs — amodiaquine, mefloquine, sulfadoxine/pyrimethamine or lumefantrine — which permit elimination of the residual malarial parasites.The clinical pharmacology of artemisinin-based combination therapies is highly complex. The short-acting artemisinins and their long-acting counterparts are metabolized and/or inhibit/induce cytochrome P450 enzymes, and may thus participate in drug-drug interactions with multiple drugs on the market. Alterations in antimalarial drug plasma concentrations may lead to either suboptimal efficacy or drug toxicity and may compromise treatment.

Pharmacokinetics and bioavailability of an integrase and novel pharmacoenhancer-containing single-tablet fixed-dose combination regimen for the treatment of HIV.

Objective: This study evaluated the relative bioavailability and pharmacokinetics of elvitegravir (EVG), emtricitabine (FTC), tenofovir disoproxil fumarate (TDF), and a investigational pharmacoenhancer, cobicistat (GS-9350, COBI) coformulated as a fixed-dose combination tablet (FDC) compared with ritonavir-boosted EVG and FTC + TDF in healthy subjects. Methods: Subjects were randomized to 1 of 2 sequences. All treatments were administered in the morning for 10 days with food, separated by a 2-day washout. Blood samples were collected over 24 hours with the last dose of each treatment. Results: Forty-four subjects enrolled, 42 subjects completed all periods. All study treatments were generally well tolerated. Relative to ritonavir-boosted EVG, the geometric least-squares means ratios (GMR) [90% confidence interval (CI)] for EVG area under plasma concentration-time curve from time zero until the end of the dosing interval (AUC)tau, maximum concentration (Cmax), and trough concentration (Ctau) were 118 (110 to 126), 108 (100 to 116), and 110 (95.3 to 127), respectively, with EVG/COBI 150 mg/FTC/TDF. Relative to FTC + TDF, FTC GMR, and 90% CI were 127 (115 to 140) for AUCtau, 121 (107 to 137) for Cmax, and 126 (118 to 136) for Ctau; tenofovir (TFV) GMR and 90% CI were 118 (114 to 122), 130 (122 to 138), and 124 (119 to 129) for AUCtau, Cmax, and Ctau, respectively, with EVG/COBI 150 mg/FTC/TDF. Conclusions: Fixed-dose combination tablet containing COBI 150 mg resulted in desired high EVG Ctau concentrations and clinically equivalent tenofovir and FTC exposures relative to currently approved individual agents and was thus selected for subsequent evaluation.

Lopinavir/ritonavir affects pharmacokinetic exposure of artemether/lumefantrine in HIV-uninfected healthy volunteers.

Objectives:Antimalarial combination therapy is used in persons with HIV infection in the absence of data on drug interactions. The objective of this study was to investigate the pharmacokinetics (PK) of antimalarial combination artemether/lumefantrine (AL) when administered with the protease inhibitor combination lopinavir/ritonavir (LPV/r) in HIV-uninfected healthy volunteers to determine if important drug interactions exist between these agents. Design:Open-label study in healthy HIV-seronegative adults. Methods:Participants received standard 6-dose treatment courses of AL 80/480 mg twice daily on days 1-4 and 28-31. LPV/r 400/100 mg twice daily was administered on days 16-41 after a 2-week washout period. Plasma concentrations of AL, dihydroartemisinin (DHA, artemether metabolite), lopinavir, and ritonavir were measured. Results:PK of lumefantrine was influenced by LPV/r resulting in 2- to 3-fold increases in area under the curve (AUC) (AUC0-264: 413 versus 931 h·μg·mL−1; AUC0-inf: 456 versus 1073 h·μg·mL−1). For artemether, trends toward Cmax and AUC decreases (Cmax 14.3 versus 11.2 ng/mL and 42.7-62.0 versus 25.9-40.5 h·ng·mL−1 for AUC) were noted during coadministration. For DHA, decreases in Cmax (58.8 versus 37.3 ng/mL) and AUC (190-198 versus 104-109 h·ng·mL−1) were observed during coadministration without changes in DHA:artemether AUC ratios. AL did not affect LPV/r PK. Conclusions:Coadministration of artmether/lumefantrine and LPV/r can be carried out for patients coinfected with malaria and HIV. Formal safety analysis of concomitant therapy should be addressed by future studies among individuals living in malaria-endemic regions.

Pharmacokinetics of Artemether-Lumefantrine and Artesunate-Amodiaquine in Children in Kampala, Uganda

ABSTRACT The World Health Organization recommends the use of artemisinin-based combination therapies (ACTs) for the treatment of uncomplicated malaria. The two most widely adopted ACT regimens are artemether (AR)-lumefantrine (LR) (the combination is abbreviated AL) and amodiaquine (AQ)-artesunate (AS). Pharmacokinetic (PK) data informing the optimum dosing of these drug regimens is limited, especially in children. We evaluated PK parameters in Ugandan children aged 5 to 13 years with uncomplicated malaria treated with AL (n = 20) or AQ-AS (n = 21), with intensive venous sampling occurring at 0, 2, 4, 8, 24, and 120 h following administration of the last dose of 3-day regimens of AL (twice daily) or AQ-AS (once daily). AS achieved an estimated maximum concentration in plasma (Cmax) of 51 ng/ml and an area under the concentration-time curve from time zero to infinity (AUC0-∞) of 113 ng·h/ml; and its active metabolite, dihydroartemisinin (DHA), achieved a geometric mean Cmax of 473 ng/ml and an AUC0-∞ of 1,404 ng·h/ml. AR-DHA exhibited a Cmax of 34/119 ng/ml and an AUC0-∞ of 168/382 ng·h/ml, respectively. For LR, Cmax and AUC0-∞ were 6,757 ng/ml and 210 μg·h/ml, respectively. For AQ and its active metabolite, desethylamodiaquine (DEAQ), the Cmaxs were 5.2 ng/ml and 235 ng/ml, respectively, and the AUC0-∞s were 39.3 ng·h/ml and 148 μg·h/ml, respectively. Comparison of the findings of the present study to previously published data for adults suggests that the level of exposure to LR is lower in children than in adults and that the level of AQ-DEAQ exposure is similar in children and adults. For the artemisinin derivatives, differences between children and adults were variable and drug specific. The PK results generated for children must be considered to optimize the dosing strategies for these widely utilized ACT regimens.

The safety and effectiveness of ledipasvir−sofosbuvir in adolescents 12‐17 years old with hepatitis C virus genotype 1 infection

No all‐oral, direct‐acting antiviral regimens have been approved for children with chronic hepatitis C virus (HCV) infection. We conducted a phase 2, multicenter, open‐label study to evaluate the efficacy and safety of ledipasvir–sofosbuvir in adolescents with chronic HCV genotype 1 infection. One hundred patients aged 12‐17 years received a combination tablet of 90 mg ledipasvir and 400 mg sofosbuvir once daily for 12 weeks. On the tenth day following initiation of dosing, 10 patients underwent an intensive pharmacokinetic evaluation of the concentrations of sofosbuvir, ledipasvir, and the sofosbuvir metabolite GS‐331007. The primary efficacy endpoint was the percentage of patients with a sustained virologic response at 12 weeks posttreatment. Median age of patients was 15 years (range 12‐17). A majority (80%) were HCV treatment‐naive, and 84% were infected through perinatal transmission. One patient had cirrhosis, and 42 did not; in 57 patients the degree of fibrosis was unknown. Overall, 98% (98/100; 95% confidence interval 93%‐100%) of patients reached sustained virologic response at 12 weeks. No patient had virologic failure. The 2 patients who did not achieve sustained virologic response at 12 weeks were lost to follow‐up either during or after treatment. The three most commonly reported adverse events were headache (27% of patients), diarrhea (14%), and fatigue (13%). No serious adverse events were reported. Area under the concentration‐time curve (tau) and maximum concentration values for sofosbuvir, ledipasvir, and GS‐331007 were within the predefined pharmacokinetic equivalence boundaries of 50%‐200% when compared with adults from phase 2 and 3 studies of ledipasvir and sofosbuvir. Conclusion: Ledipasvir−sofosbuvir was highly effective at treating adolescents with chronic HCV genotype 1 infection; the dose of ledipasvir−sofosbuvir currently used in adults was well tolerated in adolescents and had an appropriate pharmacokinetic profile. (Hepatology 2017;66:371–378).

Preclinical Pharmacokinetics and First-in-Human Pharmacokinetics, Safety, and Tolerability of Velpatasvir, a Pangenotypic Hepatitis C Virus NS5A Inhibitor, in Healthy Subjects

ABSTRACT Preclinical characterization of velpatasvir (VEL; GS-5816), an inhibitor of the hepatitis C virus (HCV) NS5A protein, demonstrated that it has favorable in vitro and in vivo properties, including potent antiviral activity against hepatitis C virus genotype 1 to 6 replicons, good metabolic stability, low systemic clearance, and adequate bioavailability and physicochemical properties, to warrant clinical evaluation. The phase 1 (first-in-human) study evaluated the safety, tolerability, and pharmacokinetics of VEL in healthy human subjects following administration of single and multiple (n = 7) once-daily ascending doses and of VEL in the presence and absence of food. Following administration of single and multiple doses, VEL was safe and well tolerated when administered at up to 450 mg and when administered with food. The pharmacokinetic behavior of VEL observed in humans was generally in agreement with that seen during preclinical characterization. Following administration of multiple doses, VEL trough concentrations were significantly greater than the protein-adjusted half-maximal (50%) effective concentration of VEL against HCV genotype 1 to 6 replicons at all evaluated doses greater than 5 mg. The pharmacokinetics of VEL were not significantly affected by administration with food. Collectively, the results of this study support the further clinical investigation of VEL administered once daily as part of a regimen with other pangenotypic direct-acting antivirals for the treatment of HCV infection.

A Thorough QT Study to Evaluate the Effects of Supratherapeutic Doses of Ledipasvir on the QTc Interval in Healthy Subjects

This study evaluated the effect of supratherapeutic exposure of the anti‐HCV drug ledipasvir on the QTc interval in healthy subjects. Sixty healthy volunteers were randomized to receive twice‐daily blinded ledipasvir (120 mg) or placebo, administered for 10 days each, or single doses of open‐label moxifloxacin (400 mg). Serial plasma samples for ledipasvir concentration analysis were collected after each treatment. Triplicate time‐matched electrocardiograms were collected at baseline and after each treatment. Change from baseline in the QTc for ledipasvir or moxifloxacin versus placebo was determined using several correction formulas (primary: QTcF [Fridericias]; secondary: QTcN [population] and QTcI [individual]). Pharmacokinetics and exposure–QTc relationships were evaluated. Ledipasvir AUC0–24 and Cmax achieved approximately 3.7‐fold and 4.2‐fold, respectively, above exposures observed following administration of ledipasvir/sofosbuvir (90/400 mg) to HCV‐infected patients. There was a lack of effect of supratherapeutic ledipasvir on QTc intervals using all correction methods (upper bound of the 2‐sided 90%CIs for the mean difference in time‐matched baseline‐corrected QTc between ledipasvir versus placebo < 10 milliseconds at all times). The lower bound of the 2‐sided 96.67%CI for the mean difference in moxifloxacin versus placebo was >5 milliseconds, thereby establishing assay sensitivity. Categorical analyses did not demonstrate clinically relevant effects of ledipasvir on QTc intervals or other electrocardiogram parameters. No relationships between ledipasvir plasma concentration and QTc interval were observed. Ledipasvir does not prolong QTc interval. Based on these results and a previous TQT evaluation for sofosbuvir, the fixed‐dose combination regimen of ledipasvir/sofosbuvir is not expected to prolong the QTc interval.

The drug-drug interaction potential of antiviral agents for the treatment of chronic hepatitis C infection

Several safe and highly effective direct-acting antiviral (DAA) drugs for chronic hepatitis C virus (HCV) have been developed and greatly increase the number of therapeutic options available to successfully treat HCV infection. However, because treatment regimens contain at least two drugs (e.g., elbasvir and grazoprevir, glecaprevir and pibrentasvir, or sofosbuvir with daclatasvir, simeprevir, ledipasvir, or velpatasvir) and up to five drugs (ombitasvir/paritaprevir/ritonavir plus dasabuvir with or without ribavirin), the potential for drug-drug interactions (DDIs) becomes an important consideration for HCV-infected individuals with comorbidities that require concomitant medications, such as human immunodeficiency virus/HCV coinfection or immunosuppression after liver transplantation. This review details the pharmacokinetics and DDI potential of approved DAAs for the treatment of HCV infection.