Biowaiver approach for biopharmaceutics classification system class 3 compound metformin hydrochloride using in silico modeling.

The dependency of metformin in vivo disposition on the rate and extent of dissolution was studied. The analysis includes the use of fundamental principles of drug input, permeability, and intestinal transit time within the framework of a compartmental absorption transit model to predict key pharmacokinetic (PK) parameters and then compare the results to clinical data. The simulations show that the maximum plasma concentration (C(max) ) and area under the curve (AUC) are not significantly affected when 100% of drug is released within 2 h of oral dosing, which was confirmed with corresponding human PK data. Furthermore, in vitro dissolution profiles measured in aqueous buffers at pH values of 1.2, 4.5, and 6.8 were slower than in vivo release profiles generated by deconvolution of metformin products that were bioequivalent. On the basis of this work, formulations of metformin that release 100% in vitro in a time period equal to or less than two hours are indicated to be bioequivalent. The use of modeling offers a mechanistic-based approach for demonstrating acceptable bioperformance for metformin formulations without having to resort to in vivo bioequivalence studies and may be more robust than statistical comparison of in vitro release profiles. This work further provides a strategy for considering Biopharmaceutics Classification System (BCS) Class 3 compounds to be included under biowaiver guidelines as for BCS Class 1 compounds.

Renal insufficiency has no effect on the pharmacokinetics of vicriviroc in a ritonavir-containing regimen.

BACKGROUND AND OBJECTIVE: Vicriviroc is a small-molecule CCR5 antagonist currently in development for the treatment of HIV in patients on a regimen containing a ritonavir-boosted protease inhibitor. As renal disease and renal dysfunction are prevalent in the HIV-infected population, patients with varying degrees of renal insufficiency may receive vicriviroc, which is metabolized by cytochrome P450 (CYP) 3A4. The present study therefore examined the impact of renal insufficiency on the pharmacokinetics and safety of vicriviroc alone and in the presence of ritonavir, a strong CYP3A4 inhibitor. SUBJECTS AND METHODS: This study was an open-label, randomized, two-treatment crossover trial conducted in HIV-negative subjects with haemodialysis-dependent end-stage renal disease (ESRD) and healthy subjects with normal renal function matched by age, height, bodyweight and sex. Subjects received a single dose of vicriviroc 75 mg alone in one period, and in another period they received a single dose of vicriviroc 15 mg after 4 days of ritonavir 100 mg once daily. Ritonavir treatment was then continued for an additional 13 days. The two trial periods were separated by an interval of at least 3 weeks. The primary endpoints were the log-transformed area under the plasma concentration-time curve (AUC) and the maximum plasma concentration (C(max)), and the 90% confidence intervals (CIs) of the mean differences between subjects with ESRD and matched healthy subjects. The protocol provided the option of dose modification and further study if the vicriviroc C(max) and AUC values were at least twice as high in subjects with ESRD compared with healthy subjects, or if warranted by other safety and tolerability observations. RESULTS: Twelve subjects (six with ESRD, six healthy) completed the study. When vicriviroc was administered alone, the mean vicriviroc C(max) and AUC ratio estimates (90% CI) for subjects with ESRD versus healthy subjects were 74% (53, 103) and 84% (49, 145), respectively. When ritonavir was added to the regimen, the ratio estimates (90% CI) were 81% (59, 111) and 134% (105, 171), respectively. Ritonavir plasma concentrations were substantially higher in subjects with ESRD than in healthy subjects. Treatment-emergent adverse events considered possibly or probably related to treatment occurred only during the ritonavir period of the study and in one healthy subject and two subjects with ESRD; all were of mild or moderate severity. CONCLUSIONS: ESRD had no clinically relevant impact on exposure of vicriviroc when vicriviroc was administered alone or in the presence of ritonavir. In this single-dose study, vicriviroc was well tolerated both by healthy subjects and by those with ESRD. Dose adjustment of vicriviroc is therefore not necessary in renally impaired populations.

Pharmacokinetic/pharmacodynamic modeling of the antiretroviral activity of the CCR5 antagonist Vicriviroc in treatment experienced HIV-infected subjects (ACTG protocol 5211).

OBJECTIVE: This substudy of AIDS Clinical Trials Group (ACTG) Protocol 5211 explored the relationship between antiretroviral effect and plasma concentrations of vicriviroc, an investigational CCR5 antagonist for HIV infection. METHODS: Eighty-six treatment-experienced subjects failing their current antiretroviral regimens were randomized to add vicriviroc 5, 10, or 15 mg once daily or placebo for 2 weeks. Beyond week 2, subjects were changed to optimized background antiretroviral treatment while continuing vicriviroc or placebo. Plasma samples collected at weeks 2 and 8 were assayed for vicriviroc concentrations and combined with vicriviroc concentration data from 110 seronegatives enrolled in 5 phase 1 studies. An inhibitory Emax model was used to assess pharmacokinetic (PK)/pharmacodynamic relationships and recursive partitioning was applied to determine the breakpoint in vicriviroc PK parameters associated with virologic suppression. RESULTS: A 2-compartment model was fitted to the drug concentration data. At week 2, a higher vicriviroc Cmin was associated with a greater mean drop in HIV RNA (viral load) and a higher percentage of subjects experiencing a >1 log10 copies/mL drop in viral load. In subjects with Cmin > 54 ng/mL, the mean viral load decrease was 1.35 log10 copies/mL vs. 0.76 log10 with Cmin < 54 ng/mL (P = 0.003, Student t test). At this Cmin breakpoint, 70% of subjects with the higher Cmin had a >1 log drop in HIV RNA, compared with 44% with a lower Cmin (P = 0.048, Fisher exact test). Similar results were seen with an area under the curve breakpoint of 1460 ng h/mL. At weeks 16 and 24, all vicriviroc-treated subjects experienced better viral load responses than placebo recipients, but there was no apparent relationship between PK and change in viral load among these vicriviroc-treated subjects. CONCLUSIONS: There was a positive correlation between vicriviroc Cmin, area under the curve, and viral load changes at week 2 in treatment-experienced HIV-infected subjects receiving no other new active antiretroviral drugs. This correlation did not persist beyond week 16, probably because treatment response at that point also depended on having other active drugs in the regimen.

Short-term administration of the CCR5 antagonist vicriviroc to patients with HIV and HCV coinfection is safe and tolerable.

OBJECTIVE: CCR5 antagonists block HIV cell entry through competitive binding to the CCR5 receptor present on the surface of CD4(+) cells. The CCR5 receptor is also present on CD8(+) cells involved in clearing hepatitis C virus (HCV). The goal of the present study was to examine the short-term safety of a CCR5 antagonist, vicriviroc, in patients with HIV/HCV coinfection. METHODS: A randomized, double-blind trial was conducted in 28 HIV/HCV-coinfected subjects with compensated liver disease and plasma HIV RNA below 400 copies/mL. All subjects were receiving a ritonavir-enhanced protease inhibitor regimen, to which vicriviroc (5, 10, or 15 mg/day) or placebo was added for 28 days. Clinical and laboratory evaluations were performed 21 days beyond the treatment period. RESULTS: Treatment with vicriviroc resulted in no clinically meaningful changes in HCV or HIV viral load or any immune parameters. Adverse events were equally distributed among placebo and vicriviroc groups. Transaminase elevations of grade 1 or more were reported as AEs in 1 subject receiving 10-mg vicriviroc and 1 placebo subject. Vicriviroc plasma concentrations were similar to those observed in healthy subjects. CONCLUSIONS: Short-term treatment with vicriviroc as part of a ritonavir-containing protease inhibitor-based regimen was safe and well tolerated in HIV/HCV-coinfected subjects. HIV/HCV coinfection also did not affect vicriviroc pharmacokinetics.

Antiviral activity, pharmacokinetics and safety of vicriviroc, an oral CCR5 antagonist, during 14-day monotherapy in HIV-infected adults.

OBJECTIVE: To determine antiviral activity, pharmacokinetic properties, and safety of vicriviroc, an orally available CCR5 antagonist, as monotherapy in HIV-infected patients. DESIGN AND METHODS: An ascending, multiple dose, placebo-controlled study randomized within treatment group. Forty-eight HIV-infected individuals were enrolled sequentially to dose groups of vicriviroc: 10, 25 and 50 mg twice a day, and were randomly assigned within group to receive vicriviroc or placebo (16 total patients/group) for 14 days. RESULTS: Significant reductions from baseline HIV RNA after 14 days were achieved in all active treatment groups. Suppression of viral RNA persisted 2-3 days beyond the end of treatment. Reductions of 1.0 log10 HIV RNA or greater were achieved in 45, 77 and 82% of patients in the three groups, respectively. Eighteen, 46 and 45% of subjects achieved declines of 1.5 log10 or greater in HIV RNA in the three groups, respectively. Vicriviroc was rapidly absorbed with a half-life of 28-33 h, supporting once-daily dosing. Pharmacokinetic parameters were dose linear; steady state was achieved by day 12. Two subjects experienced a transient detectable X4-tropic virus. Vicriviroc was well tolerated in all dose groups. The frequency of adverse events was similar in the vicriviroc and placebo groups: 72 and 62%, respectively. The most frequently reported adverse events included headache, pharyngitis, nausea and abdominal pain, which were not dose related. CONCLUSION: Whereas all doses were well tolerated and produced significant declines in plasma HIV RNA, total oral daily doses of 50 or 100 mg vicriviroc monotherapy for 14 days appeared to provide the most potent antiviral effect in this study.

Desloratadine has no clinically relevant electrocardiographic or pharmacodynamic interactions with ketoconazole.

OBJECTIVE: This study was performed to assess the electrocardiographic safety and pharmacokinetics of desloratadine in combination with the CYP3A4 inhibitor ketoconazole. DESIGN: A randomised, placebo-controlled, third-party-blind, 2-way crossover study. PARTICIPANTS: 24 healthy volunteers (12 men, 12 women; age 19 to 50 years). INTERVENTIONS: 7.5mg of desloratadine orally per day in combination with placebo or with 200mg of ketoconazole every 12 hours for 10 days. After a minimum 7-day washout period, participants received the alternative treatment. MAIN OUTCOME MEASURES: ECG parameters. RESULTS: Comparable maximum corrected QT (QT(c)) intervals were observed after coadministration of desloratadine and placebo or ketoconazole (431 and 435 msec, respectively). The desloratadine/ketoconazole combination did not induce any statistically significant or clinically relevant changes in QT(c), QT, PR or QRS intervals compared with desloratadine alone; ventricular rate was slightly slower when desloratadine was given with ketoconazole. At steady state, coadministration of ketoconazole resulted in no significant change in area under the desloratadine concentration-time curve (AUC) from 0 to 24 hours compared with desloratadine/placebo. Coadministration of desloratadine and ketoconazole resulted in a 1.3-fold increase in desloratadine maximum concentration (C(max)) that was not clinically relevant. The most common adverse event was headache, reported in 42 and 38% of individuals, respectively, after coadministration of desloratadine/placebo and desloratadine/ketoconazole. There were no reports of dizziness or syncope. CONCLUSION: Coadministration of desloratadine and ketoconazole was well tolerated and was associated with minimal increase in AUC and C(max). The combination did not induce any clinically relevant electrocardiographic changes.