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BI 201335 pharmacokinetics and early effect
on viral load in HCV genotype-1 patients
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Reported by Jules Levin
EASL 2011 Berlin Germany March 30-Apr 2
Chan-Loi Yong,1 Joe Scherer,1 John Sabo,1 Jerry Stern,1 Gerd Steinmann,2 Wulf O. Boecher2
1Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA; 2Boehringer Ingelheim Pharma GmbH, Biberach, Germany
EASL: Positive Phase 2 results reported with Boehringer Ingelheim's investigational HCV protease inhibitor in both previously treated and untreated patient - (04/04/11)
EASL: SILEN-C1: sustained virological response (SVR) and safety of BI 201335 combined with peginterferon alfa 2a and ribavirin (PegIFN/RBV) in treatment-naïve patients with chronic genotype-1 HCV infection - (04/01/11)
EASL: SILEN-C2: sustained virological response (SVR) and safety of BI 201335 combined with peginterferon alfa 2a and ribavirin (PegIFN/RBV) in chronic HCV genotype-1 patients with nonresponse to PegIFN/RBV - (04/01/11)
EASL: Boehringer Ingelheim's Lead Hepatitis C Compound Moves into Phase 3 - the First Within the BI HCV Portfolio - (04/04/11)
AUTHOR CONCLUSIONS
· BI 201335 exposure increased more than proportionately with dose
· The addition of PegIFN/RBV to BI 201335 monotherapy had no effect on the PK of BI 201335
· There was a clear correlation of viral decay with PK exposure on monotherapy but not on combination therapy
· At the 240 mg dose level, approximately 50% of steady state exposure was attained after the two-fold loading dose on Day 1, compared with approximately 15% attained without a loading dose
· T1/2 at steady state was 21-33 hours, supporting QD dosing
ABSTRACT
Background: BI 201335 is a highly potent and specific hepatitis C virus (HCV) NS3/4A protease inhibitor in clinical development. Here, we describe the pharmacokinetics (PK) and the modelling of PK/pharmacodynamic (PD) correlation in a 28-day phase I trial (1220.2) in HCV genotype-1 (GT-1) patients.
Methods: In a double-blinded, multiple rising-dose part, HCV GT-1 patients were treated for 28 days with placebo or increasing doses of BI 201335: (i) treatment-naïve (TN) with 20, 48, 120 and 240 mg once daily (QD) oral solution from D1-28, and peginterferon and ribavirin PegIFN/RBV added at D15-29; and (ii) treatment-experienced (TE) with 48, 120 and 240 mg QD solution with PegIFN/RBV from D1-29. In an open-label parallel group part, TE patients were randomised to 240 mg QD versus twice daily capsules and P/R for 28 days. Plasma viral load (VL) was measured by Roche COBAS TaqMan v2. Plasma concentrations of BI 201335 were measured using high-performance liquid chromatography coupled to mass spectrometry. Linear regression and bootstrap analyses were performed to model the PK/PD correlation.
Results: During the first days of monotherapy, VL decreased in a BI 201335 concentration-dependent manner. Steady-state drug exposure increased more than proportionately with dose. No or little effect of PegIFN/RBV on BI 201335 exposure was found. Interindividual variability was moderately high (CVAUC ~60%). Steady-state was attained in ~6 days, and half-life was ~20-30 hours. VL reduction in TN patients was highly correlated with trough concentrations (see Figure) and can be expressed as power function up to about 6-10 days during BI 201335 monotherapy. Minimal PK/PD correlation was found in TE on combination therapy.
Conclusions: BI 201335 exposure increased more than proportionately with dose, with a clear correlation to viral decay on mono- but not PegIFN/RBV combination-therapy. PK characteristics support QD dosing. This compound is currently in phase III of clinical development.
INTRODUCTION
BI 201335 is a highly potent and specific hepatitis C virus (HCV) NS3/4A protease inhibitor in clinical development
The relationship between BI 201335 plasma trough concentration and plasma viral load (VL) was investigated
The pharmacokinetics (PK) of BI 201335 during 2 weeks' monotherapy, and in combination with peginterferon alfa 2a/ribavirin (PegIFN/RBV) for 2 additional weeks, in treatment-naïve (TN) HCV patients was determined
The PK of BI 201335 coadministered with PegIFN/RBV for 4 weeks in treatment-experienced (TE) HCV patients was also determined
METHODS
In a double-blind, multiple rising-dose part of the clinical study, HCV genotype-1 patients were treated for 28 days with placebo or increasing doses of BI 201335
-- TN patients were treated with 20, 48, 120 or 240 mg BI 201335 oral solution once daily (QD) for 28 days; PegIFN (180 μg/week subcutaneous) and RBV (weight based: 1,000 mg or 1,200 mg daily) were added at Days 15-28
-- TE patients were treated with 48, 120 or 240 mg BI 201335 QD, plus PegIFN/RBV, for 28 days
In an open-label, parallel group part of the clinical study, TE patients were randomised to 240 mg BI 201335 QD versus twice daily (BID) soft gelatin capsules (SGC), plus PegIFN/RBV, for 28 days
-- for TE patients in cohorts IX and X, who received SGC, a 480 mg loading dose was administered as the first dose
All patients were offered continuation of treatment with PegIFN/RBV until Week 48
The treatment cohorts for TN and TE patients are summarised in Table 1
Plasma VL samples and trough plasma BI 201335 samples were collected at each visit on Day 1 (baseline), 2, 3, 4, 6, 10, 14, 21 and 28
Plasma concentration-time profiles for BI 201335 were obtained on Days 1, 14 and 28 for TN patients, and on Day 1 and 28 for TE patients
Plasma VL was measured by Roche COBAS TaqMan v2 with a lower limit of quantification of 25 IU/mL and a lower limit of detection of 10 IU/mL
Plasma concentrations of BI 201335 were measured using HPLC-MS/MS
PK parameters were obtained using noncompartmental analysis
Linear regression and bootstrap analyses evaluated the PK/pharmacodynamic (PD) relationship by day using the pooled data for all treatment groups in the TN and TE cohorts
PK of BI 201335
· In TN patients who received active drug for 4 weeks in the solution formulation, steady-state was attained at approximately 120 hours (Day 6)
· Considerably higher concentrations (up to ~5-fold higher) were observed at steady-state than at 24 hours after the initial dose
· Geometric mean trough (predose) plasma concentrations of BI 201335 in TN patients are depicted in Figure 1
· Steady-state drug exposure of BI 201335 increased more than proportionately with dose in TN patients for Cmax,ss, Cmin,ss, and AUCτ,ss obtained on Day 28 as summarised in Table 2 and Figure 2A
--oral clearance of BI 201335 decreased with dose
· Comparison of PK parameters at Day 14 and Day 28 showed little or no effect of PegIFN/RBV on BI 201335 exposure
· Interindividual variability was moderately high with coefficient of variation (CV) values mostly around 50%-60% for AUCτ,ss
· Steady-state half-life of BI 201335 was ~20-30 hours, which indicates that it is suitable for QD dosing
· Similar PK parameters were observed in TE patients on Day 28 (Table 3 and Figure 2B) compared with TN patients
· At steady state, BI 201335 exposure after SGC appeared to be slightly higher than solution at this dose level, but in general, exposure was similar between SGC and solution
· A 480 mg loading dose, administered on Day 1 for the 240 mg QD dose group, resulted in attaining approximately 50% of steady state exposure on Day 1; whereas approximately 15% was attained when no loading dose was administered
PK/PD relationship
· For TN patients during the earlier days of BI 201335 monotherapy, VL decreased in a dose- and concentration-dependent manner
· The median change in VL from baseline was largest at Day 4 for the 20, 48 and 120 mg solution dose groups (-2.87, -3.56 and -3.63 log10 IU/mL, respectively), and at Day 6 for the 240 mg solution dose group (-4.11 log10 IU/mL)
--clinical results have been presented previously elsewhere1,2
· VL reduction in TN patients was highly correlated with trough concentration and can be expressed as a power function up to about 6-10 days during BI 201335 monotherapy as shown in Figure 3
FIGURE 3. Relationship of plasma BI 201335 Cmin (nmol/L) to the change in VL for TN patients (solid circles are VL and Cmin values for individual patients; solid line is the least-square mean; broken line is the 95% confidence limit for the mean)
Plasma BI 201335 concentration (nmol/L)
· The dependence of VL on concentration of BI 201335 was greatest at early treatment times (slope = -1.30 on Day 2) and gradually decreased with increased treatment duration
· The dose- and concentration-dependency in median VL decrease was much less pronounced on combination therapy (TE patients) than on monotherapy (TN patients)
· The relationship between AUC0-24h and Cmax to the change in VL in TN patients is shown in Figure 4
· The relationship of the change in VL from baseline to plasma BI 201335 concentration was explored in greater depth by linear regression. The equation describing the change in VL on each day is:
Change in VL = (slope of log10 BI 201335 concentration [nmol/L]) + intercept
--the slope and intercept can be the observed mean or the resampled (bootstrap) mean
· Overall, the TN patient group demonstrated a clear concentration- and time-dependent reduction in VL on monotherapy (Table 4)
References
1. Manns MP, et al. Potency, safety and pharmacokinetics of the NS3/4A protease inhibitor BI201335 in patients with chronic HCV genotype-1 infection. J Hepatol 2010 Nov 11 [Epub ahead of print].
2. Berg T, et al. Virological response and safety of 4 weeks' treatment with the protease inhibitor BI 201335 combined with 48 weeks of peginterferon alfa 2a and ribavirin for treatment of HCV GT-1 patients who failed peginterferon/ribavirin. Hepatology 2010;52(Suppl. 1) Abstract 804.
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