[Show abstract][Hide abstract] ABSTRACT: Faldaprevir is a potent hepatitis C virus (HCV) NS3/4A protease inhibitor with negligible urinary excretion. We assessed the
pharmacokinetics and safety of a single oral dose of faldaprevir (480 mg) in 32 HCV-negative subjects with renal impairment
or normal renal function. Compared with subjects with normal renal function, the adjusted geometric mean ratios (90% confidence
intervals in parentheses) for overall exposure area under the concentration-time curve from zero to infinity (AUC0–∞) were 113.6% (41.6 to 310.2%), 178.3% (85.2 to 373.0%), and 169.2% (73.2 to 391.2%) for subjects with mild, moderate, and
severe renal impairment, respectively. Overall, 5/8 (63%) subjects with normal renal function and 20/24 (83%) subjects with
renal impairment reported adverse events, with gastrointestinal events being the most common. No severe or serious adverse
events or deaths were reported. These results suggest that moderate or severe renal impairment can result in a modest increase
in faldaprevir exposure. The increase in exposure may be related to decrease in the activity of the liver uptake transporter
OATP1B1 as a result of renal impairment. Given this relatively slight increase in exposure, a dose adjustment in HCV patients
with renal impairment is not warranted. (This study has been registered at ClinicalTrials.gov under registration number NCT01957657.)
[Show abstract][Hide abstract] ABSTRACT: The pharmacokinetics, mass-balance and metabolite profiles of faldaprevir, a selective peptide-mimetic Hepatitis C NS3/NS4 protease inhibitor, were assessed at steady state in 7 healthy male subjects. Subjects received oral doses of 480 mg faldaprevir on Day 1, followed by 240 mg faldaprevir on Days 2 to 8 and 10 to 15. [(14)C]-faldaprevir (240 mg containing 100 μCi) was administered on Day 9. Blood, urine, feces and saliva samples were collected at intervals throughout the study. Metabolite profiling was performed using radiochromatography, and metabolite identification was conducted using liquid chromatography/tandem mass spectrometry. The overall recovery of radioactivity was high (98.8%), with the majority recovered from feces (98.7%). There was minimal radioactivity in urine (0.113%) and saliva. Circulating radioactivity was predominantly confined to plasma with minimal partitioning into red blood cells. The terminal half-life of radioactivity in plasma was approximately 23 hours with no evidence of any long-lasting metabolites. Faldaprevir was the predominant circulating form accounting for 98-100% of plasma radioactivity from each subject. Faldaprevir was the only drug-related component detected in urine. Faldaprevir was also the major drug-related component in feces representing 49.8% of the radioactive dose. The majority of the remainder of radioactivity in feces (41% of the dose) was accounted for in almost equal quantities by 2 hydroxylated metabolites. The most common adverse events were nausea, diarrhea and constipation all of which were related to study drug. In conclusion, faldaprevir is predominantly excreted in feces with negligible urinary excretion.
[Show abstract][Hide abstract] ABSTRACT: To compare steady-state (ss) pharmacokinetic (PK) targets of nevirapine extended-release (NVP-XR) tablets once-daily (QD) with immediate-release (NVP-IR) tablet or oral suspension twice-daily (BID) in HIV-1 infected children and adolescents.
Phase I, open-label, multi-dose, cross-over study with optional extension phase, in 85 patients 3 to <18 years old, previously on an NVP-IR based regimen for 18 weeks with baseline viral load <50 copies/mL. Patients were stratified by age, treated with NVP-IR BID for 11 days, then NVP-XR QD for 10 days. Cpre,ss (steady state, pre-dose concentrations) was obtained from all, and 12-h NVP-IR and 24-h NVP-XR steady state PK profiles were obtained in the PK sub-study. Viral loads, CD4 counts and adverse events (AEs) were monitored.
Eighty patients completed the trial. Adjusted geometric mean (gMean) Cpre,ss for NVP-XR and NVP-IR exceeded the target of 3,000 ng/mL, and the adjusted gMean NVP-XR:NVP-IR ratio (90% CI) for QD normalized and un-normalized Cpre,ss were 91.2% (83.5%,99.6%) and 91.8% (83.7%, 100.7%). gMean 24-h AUC,ss NVP-XR:NVP-IR for un-normalized dose was 90.4% and un-normalized Cpre,ss NVP-XR:NVP-IR were 91.0%, 81.9%,103.7% for the three age groups, 3 to<6 y, 6 to <12 y, and 12 to <18 y, respectively. gMean values indicated no exposure to subtherapeutic NVP concentrations and viral suppression was adequate and maintained in all QD groups. Most AEs were mild and similar between age groups. No serious or DAIDS Grade 4 AEs or AE related treatment discontinuations occurred.
NVP-XR exhibited adequate trough concentrations with equivalent AUCτ,ss relative to NVP-IR. NVP-XR was well tolerated and is a valuable treatment option for HIV-infected children and adolescents.
[Show abstract][Hide abstract] ABSTRACT: The present study describes the cross-species absorption, metabolism, distribution and pharmacokinetics of BI 201335, a potent HCV protease inhibitor currently in phase III clinical trials. BI 201335 showed a good Caco-II permeability (8.7 × 10(-6) cm/sec) and in vitro metabolic stability (predicted hepatic clearence (CL(hep)) <19% Q(h) in all species tested). Single dose PK revealed a clearance of 17, 3.0 and 2.6 mL/min/kg in rat, monkey and dog respectively, with a corresponding oral bioavailability of 29.1, 25.5 and 35.6%. Comparative plasma and liver PK profile in rodents showed a high liver Kp in the rat (42-fold), suggesting high target tissue distribution. Simple allometry based on animal PK predicted a human oral CL/F of 168 mL/min, within two-fold of the observed value (118 mL/min) at 240 mg in healthy volunteers. Allometry of volume of distribution generated a low exponent of 0.59, and a much lower predicted Vss/F (5-fold less than observed). Several different approaches of Vss/F prediction were evaluated and compared with the value observed in human. The averaged Vss/F from preclinical animals provides the best estimation of the observed human value (169 L vs. 175 L). Corresponding human "effective" t(1/2) values were also compared. The predicted human t(1/2) based on the CL from allometry with metabolic corrections and the averaged animal Vss represented the best estimation of the clinical data (12.1 vs. 17.2 hr). The present study demonstrated that the good preclinical ADMEPK profile of BI 201335 is consistent with that observed in the clinic. While preclinical data accurately predicted the human CL, the prediction of human Vss seems to be more challenging. The averaged Vss/F from all tested preclinical animals provided the best prediction of human Vss and the resulting "effective" t(1/2).
[Show abstract][Hide abstract] ABSTRACT: Nevirapine (NVP) is a widely used non-nucleoside reverse transcriptase inhibitor. A once-daily extended-release (XR) formulation would potentially increase adherence and thus efficacy.
The aim of this study was to investigate the steady-state bioavailability of 2 once-daily tablet formulations of NVP XR (containing 25% or 20% hypromellose; NVP XR25 and NVP XR20, respectively) in 400- or 300-mg tablets compared with twice-daily immediate-release (IR) NVP 200-mg tablets.
This Phase Ib multinational, multicenter, open-label trial was conducted in patients aged 18 to 60 years, infected with HIV-1 (viral load, ≤50 copies/mL), and treated for ≥12 weeks with twice-daily NVP IR 200 mg. Patients were switched to NVP XR25 400 or 300 mg or NVP XR20 400 or 300 mg for 19 days. Plasma samples were collected over 24-hour periods at steady state. Primary end points were AUC(0-24,ss), C(max,ss), and C(min,ss), analyzed using an ANOVA statistical model on the logarithmic scale and 2-sided 90% CI. Sample size was determined assuming an intrasubject %CV of 20% for C(max). Adverse events (AEs) and viral loads were monitored.
Ninety-two patients were enrolled (NVP XR25 400 mg, 24 patients; NVP XR20 400 mg, 24; NVP XR25 300 mg, 21; NVP XR20 300 mg, 23). Compared with NVP IR, the AUC(0-24,ss) values of the NVP XR formulations were lower (test/reference ratios: 79.5% [90% CI, 73.0-86.7; P = 0.544], 71.0% [90% CI, 63.3-79.7; P = 0.956], 90.3% [90% CI, 80.4-101.4; P = 0.044], and 83.7% [90% CI, 77.9-89.9; P = 0.148] with NVP XR25 400 mg, NVP XR20 400 mg, NVP XR25 300 mg, and NVP XR20 300 mg, respectively). The relative bioavailability of NVP XR25 was greater compared with that of NVP XR20. C(max,ss) values were lower with all NVP XR formulations compared with NVP IR. For C(min,ss), NVP XR25 400 and 300 mg were not significantly different from NVP IR, with 90% CIs within the range of 80% to 125% (P = 0.039 and P = 0.017, respectively). All AEs were mild or moderate, with no significant differences between treatment groups. No virologic failures (viral load, >50 copies/mL over 2 consecutive readings) were observed.
Extent of bioavailability was lower and t(max,ss) was delayed with all NVP XR formulations compared with NVP IR. The bioavailability of the NVP XR25 formulations was greater than that of the NVP XR20 formulations. C(min,ss) with NVP XR25 was similar to that with NVP IR. All of the NVP XR formulations were well tolerated. The 400-mg NVP XR25 formulation was selected for further development.
[Show abstract][Hide abstract] ABSTRACT: This study (VERxVE) compared the efficacy and safety of the new nevirapine extended-release (NVP XR) formulation dosed once daily with NVP immediate release (IR) twice daily in treatment-naive patients.
Randomized, double-blind, double-dummy, parallel group study of HIV-1-infected adult patients with baseline viral load (VL) ≥ 1,000 copies/ml and CD4(+) T-cell count of >50-<400 (males) and >50-<250 cells/mm(3) (females). Patients stratified by baseline VL (≤ 100,000/>100,000 copies/ml) were randomized 1:1 to NVP XR 400 mg once daily (plus placebo) or NVP IR 200 mg twice daily (plus placebo), both combined with tenofovir disoproxil fumarate (TDF) 300 mg and emtricitabine 200 mg once daily. Primary endpoint was sustained virological response (<50 copies/ml) through week 48 using the time to loss of virological response algorithm. Non-inferiority of NVP XR to NVP IR was tested using Cochran's statistic incorporating baseline VL stratum with pre-specified, non-inferiority margin of -10%.
Among 1,011 patients randomized and treated, virological response at week 48 was 81.0% (409/505) for NVP XR and 75.9% (384/506) for NVP IR with adjusted difference of 4.9% in favour of NVP XR (95% CI -0.1-10.0%), demonstrating non-inferiority of NVP XR to NVP IR. This finding was supported by secondary endpoints. The safety profile of NVP XR was similar to NVP IR, but showed numerically fewer treatment-related adverse events.
NVP XR in combination with TDF and emtricitabine was shown to be non-inferior in efficacy to NVP IR with a similar safety and adverse event profile, with the potential for the added convenience of once-daily dosing. Trial registration: ClinicalTrials (NCT): NCT00561925.
[Show abstract][Hide abstract] ABSTRACT: BI201335 is a highly specific and potent HCV protease inhibitor. This multiple rising dose trial evaluated antiviral activity and safety in chronic HCV genotype-1 patients.
Thirty-four treatment-naïve patients were randomized to monotherapy with placebo or BI201335 at 20-240 mg once-daily for 14 days, followed by combination with pegylated interferon alfa/ribavirin (PegIFN/RBV) through Day 28. Nineteen treatment-experienced patients received 48-240 mg BI201335 once-daily with PegIFN/RBV for 28 days. HCV-RNA was measured with Roche COBAS TaqMan.
In treatment-naïve patients, median maximal viral load (VL) reductions during 14-day monotherapy were -3.0, -3.6, -3.7, and -4.2 log(10) for the 20, 48, 120, and 240 mg groups. VL breakthroughs (≥1 log(10) from nadir) were seen in most patients on monotherapy and were caused by NS3/4A variants (R155K, D168V) conferring in vitro resistance to BI201335. Adding PegIFN/RBV at Days 15-28 led to continuous viral load reductions in most patients. In treatment-experienced patients, treatment with BI201335 and PegIFN/RBV achieved VL<25 IU/ml at Day 28 in 3/6, 4/7, and 5/6 patients in the 48, 120, and 240 mg dose groups. VL breakthroughs were observed during triple combination in only 3/19 patients. BI201335 was generally well tolerated. Mild rash or photosensitivity was detected in four patients. Mild unconjugated hyperbilirubinemia was the only dose-dependent laboratory abnormality of BI201335. BI201335 elimination half-life supports once-daily dosing.
BI201335 combined with PegIFN/RBV was well tolerated and induced strong antiviral responses. These results support further development of BI201335 in HCV genotype-1 patients.
Journal of Hepatology 11/2010; 54(6):1114-22. DOI:10.1016/j.jhep.2010.08.040 · 11.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: An in vitro-in vivo correlation (IVIVC) for four nevirapine extended release tablets with varying polymer contents was developed. The pharmacokinetics of extended release formulations were assessed in a parallel group study with healthy volunteers and compared with corresponding in vitro dissolution data obtained using a USP apparatus type 1. In vitro samples were analysed using HPLC with UV detection and in vivo samples were analysed using a HPLC-MS/MS assay; the IVIVC analyses comparing the two results were performed using WinNonlin. A Double Weibull model optimally fits the in vitro data. A unit impulse response (UIR) was assessed using the fastest ER formulation as a reference. The deconvolution of the in vivo concentration time data was performed using the UIR to estimate an in vivo drug release profile. A linear model with a time-scaling factor clarified the relationship between in vitro and in vivo data. The predictability of the final model was consistent based on internal validation. Average percent prediction errors for pharmacokinetic parameters were <10% and individual values for all formulations were <15%. Therefore, a Level A IVIVC was developed and validated for nevirapine extended release formulations providing robust predictions of in vivo profiles based on in vitro dissolution profiles.
[Show abstract][Hide abstract] ABSTRACT: This study investigated absorption of nevirapine (NVP) from targeted sites of the gastrointestinal tract using remotely activated capsules and gamma scintigraphy. A total of 24 participants were randomized to receive 50 mg NVP orally as a suspension or via remotely activated capsules for release into the ascending colon. The 24 participants were then rerandomized into parallel groups of n = 8 for drug release into the ileum, jejunum, or descending colon. The mean gastric emptying time of capsules ranged from 0.88 to 3.35 hours. The small intestinal and colon transit time ranged from 4.08 to 7.76 hours and 17.6 to 21.2 hours, respectively, and capsule recovery time ranged from 27.6 to 34.4 hours. The relative bioavailability ratio of NVP in the jejunum was 1.06 (90% confidence interval [CI]: 1.00-1.12) compared to suspension. In the ileum, ascending colon, and descending colon, bioavailability decreased to 0.89 (0.80-0.99), 0.82 (0.71-0.95), and 0.58 (0.22-1.53), respectively. The absorption rate decreased by approximately 10-fold from the jejunum (3.83 h(-1)) to the descending colon (0.338 h(-1)), and t(max) increased from 2.42 hours (jejunum) to 16.3 hours (descending colon). Overall, NVP is absorbed from all 4 sites of the gastrointestinal tract, and the rate of absorption decreased from the jejunum to the descending colon. Relative bioavailability of NVP was in the order of jejunum > ileum > ascending colon > descending colon.
The Journal of Clinical Pharmacology 09/2009; 49(12):1417-25. DOI:10.1177/0091270009344856 · 2.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BILN-2061, a specific and potent peptidomimetic inhibitor of the HCV NS3 protease, has recently been shown to markedly lower serum hepatitis C virus (HCV)-RNA levels in patients chronically infected with HCV genotype 1 in three 2-day proof of principle studies. The aim of the current study was to assess the antiviral efficacy of BILN-2061 in patients with genotypes 2 and 3 HCV infection. The antiviral efficacy, pharmacokinetics, and tolerability of 500 mg twice-daily BILN-2061 given as monotherapy for 2 days in 10 patients chronically infected with non-genotype 1 HCV (genotype 2: n = 3; genotype 3: n =7) and minimal liver fibrosis (Ishak score 0-2) were assessed in a placebo-controlled (placebo n = 2), double-blind pilot study. HCV-RNA levels decreased by > or =1 log(10) copies/mL in 4 of 8 patients treated with BILN-2061. One patient showed a weak response of <1 log(10) copies/mL. Three of 8 treated patients showed no response. There was no correlation between baseline viral concentration or genotype and response. BILN-2061 exhibited good systemic exposure after oral administration and was well tolerated. In conclusion, the antiviral efficacy of the HCV serine protease inhibitor BILN-2061 is less pronounced and more variable in patients with HCV genotype 2 or 3 infection compared with previous results in patients with HCV genotype 1. A lower affinity of BILN-2061 for the NS3 protease of genotypes 2 and 3 HCV is most likely a major contributor to these findings.
[Show abstract][Hide abstract] ABSTRACT: Novel, potent, and well-tolerated hepatitis C virus (HCV) drugs are needed. BILN 2061 is a potent and specific inhibitor of HCV serine protease in vitro. Preclinical toxicology data and studies in healthy volunteers supported the administration of BILN 2061 to patients with HCV infection.
The antiviral efficacy, pharmacokinetics, and tolerability of 25, 200, and 500 mg BILN 2061 twice daily given as monotherapy for 2 days in 31 patients infected with chronic genotype 1 HCV infection and with minimal liver fibrosis (Ishak score of 0-2) were assessed in a placebo-controlled, double-blind pilot study. In 2 subsequent placebo-controlled studies of similar design, 200 mg BILN 2061 twice daily was administered for 2 days to 10 patients with advanced liver fibrosis (Ishak score of 3 or 4) and to 10 patients with compensated cirrhosis (Ishak score of 5 or 6).
Viral RNA reductions of 2-3 log 10 copies/mL were achieved in most of the patients. There was a trend toward a higher number of patients receiving 500 mg BILN 2061 achieving a viral RNA reduction > or =3 log(10) copies/mL as compared with patients receiving 25 mg BILN 2061. Advanced fibrosis or compensated cirrhosis did not affect the antiviral efficacy of BILN 2061. BILN 2061 was well tolerated in all studies.
BILN 2061 is a well-tolerated and very active compound that reduced serum viral RNA concentrations after 2 days of treatment in patients infected with genotype 1 HCV independent of the degree of fibrosis. Nevertheless, further clinical trials are on hold pending resolution of animal toxicity issues.
[Show abstract][Hide abstract] ABSTRACT: Hepatitis C virus (HCV) infection is a serious cause of chronic liver disease worldwide with more than 170 million infected individuals at risk of developing significant morbidity and mortality. Current interferon-based therapies are suboptimal especially in patients infected with HCV genotype 1, and they are poorly tolerated, highlighting the unmet medical need for new therapeutics. The HCV-encoded NS3 protease is essential for viral replication and has long been considered an attractive target for therapeutic intervention in HCV-infected patients. Here we identify a class of specific and potent NS3 protease inhibitors and report the evaluation of BILN 2061, a small molecule inhibitor biologically available through oral ingestion and the first of its class in human trials. Administration of BILN 2061 to patients infected with HCV genotype 1 for 2 days resulted in an impressive reduction of HCV RNA plasma levels, and established proof-of-concept in humans for an HCV NS3 protease inhibitor. Our results further illustrate the potential of the viral-enzyme-targeted drug discovery approach for the development of new HCV therapeutics.
[Show abstract][Hide abstract] ABSTRACT: The purpose of this parallel treatment group, double-blind. multicenter study was to lharacterize the pharmacokinetics of
nevirapine and lamivudine when coadministered to patients with the HIV-1 infection. This pharmacokinetic interaction study
was nested within a larger Phase III clinical trial conducted to characterize the safety and efficacy of coadministered nevirapine
and lamivudine. One hundred HIV-1 infected patients with CD4+ lymphocyte counts=200 cells/mm3 and who were on a background of nucleoside (zidovudine [ZDV], didanosine [ddl], zalcitabine [ddC], stavudine [d4T]) therapy
were randomly assigned to be treated with either nucleoside+ lamivudine+nevirapine or nucleoside+lamivudine+ placebo. Each
patient underwent blood sampling at defined times for the purpose of determining the concentration of nevirapine in plasma
and lamivudine in serum under steady-state conditions. Each patient was also monitored closely for concomitant administration
of other drugs, including ZDV, ddl, ddC, d4T and cotrimoxazole. The pharmacokinetics of nevirapine and lamivudine were characterized
using nonlinear mixed-effects modeling. There were no reported serious adverse events during the 40-day pharmacokinetic study.
The results of the modeling analysis revealed that nevirapine had no effect on the pharmacokinetics of lamivudine. Estimates
of the apparent clearance for nevirapine (CL/F=3.3 L/hour; 95% confidence interval [Cl] 2.9 to 3.7 L/hour) and lamivudine
(CL/F 27.6 L/hour; 95% Cl 22 to 33.2 L/hour) were consistent with the values reported in earlier trials. However, the results
also showed that concomitant administration of lamivudine with cotrimoxazole resulted in a 31% reduction in the apparent clearance
of lamivudine, resulting in a 43% increase in the average steady-state lamivudine serum concentrations. These results indicate
that chronic concurrent administration of cotrimoxazole with lamivudine may significantly affect the steady-state pharmacokinetics
Key WordsNevirapine-Lamivudine-Drug Interaction-Enzyme Induction-Cotrimoxazole
The AAPS Journal 03/2000; 2(1):1-8. DOI:10.1208/ps020101 · 3.80 Impact Factor