Pharmacokinetics and Tolerability of the HCV Protease Inhibitor ABT-450

Pharmacokinetics and Tolerability of the HCV Protease Inhibitor ABT-450 Following Single Ascending Doses in Healthy Adult Volunteers with and Without Ritonavir

Reported by Jules Levin
HepDART 2009 • 06-10 December 2009 • Kohala Coast, Hawaii, USA


Rajeev M Menon, Cheri E Klein, Abedayo A Lawal, Yi-Lin Chiu, Walid M Awni, Thomas J Podsadecki, Adel Nada, Barry M Bernstein (Abbott, Abbott Park, IL USA)
Corresponding author: Rajeev Menon, Abbott, 100 Abbott Park Road, Dept. R4PK, AP13A, Abbott Park, IL 60064, USA


AUTHOR CONCLUSIONS

ABT-450 with and without ritonavir was generally safe and well tolerated following single oral doses.

Increasing the ABT-450 dose fold from 300 mg to 900 mg increased the Cmax and AUC of ABT-450 in a greater than dose-proportional manner.

Ritonavir co-administration results in significant increases in ABT-450 exposure.

At ABT-450 300 mg, coadministration with ritonavir 100 mg increased the AUC for ABT-450 by ~48 fold, and increased the Cmax by ~28 fold.

The mean terminal t1/2 for ABT-450 was ~5 to 8 hours when ABT-450 was co-administered with ritonavir and was ~ 3 hours when ABT-450 was administered alone.

Consistent with the nonlinearity observed in the pharmacokinetics of ABT-450 alone, the pharmacokinetics of ABT-450 with ritonavir increased in a similar non-proportional manner.

Mean ritonavir Cmax and AUC values appear to increase with increase in ABT-450 exposure. Apparent differences in ritonavir pharmacokinetics among the dose groups may be attributed to possible effect of ABT-450 on ritonavir and cross group comparison.

Food had a minimal effect on the pharmacokinetics of ABT-450.

INTRODUCTION

ABT-450 is a potent acylsulfonamide protease inhibitor of the hepatitis C virus (HCV) being developed for the treatment of HCV genotype 1 infection.

Preclinical data suggest that ABT-450 is metabolized primarily by cytochrome P450 3A4 (CYP3A4).

Preclinical data suggested that dosing with ritonavir (RTV), a potent CYP3A4 inhibitor, would be needed in order to achieve efficacious exposures at acceptable dosing frequency.

ABT-450 has shown inhibitory concentrations in the sub-nanomolar range in genotype 1a and 1b subgenomic replicon systems in the absence of serum.

Single and multiple ascending dose studies have been conducted with ABT-450.

Results from the single dose study are described here and results from the multiple dose study are described in Poster # 58.1

METHODS

Study Design

This was a Phase 1, single-dose, randomized, placebo-controlled, parallel group study conducted according to a sequential design. The study consisted of 2 substudies. Substudy 1 dosed subjects with ABT-450 without ritonavir. In Substudy 2, ABT-450 was administered with ritonavir

Adult male and female subjects in general good health were selected to participate in the study according to the selection criteria. Three groups of eight subjects were randomized in a 3:1 fashion to receive a single oral dose of
ABT-450 or matching placebo. Additional groups of eight subjects in general good health were randomized in a 3:1 ratio (active:placebo) to receive single escalating doses of ABT-450 in combination with ritonavir. Safety, tolerability, and preliminary pharmacokinetic results were assessed in each group prior to the start of the next group.

ABT-450 was dosed alone at 300 mg, 600 mg, and 900 mg. The ABT-450 doses with ritonavir ranged from 25/100 mg ABT-450/r to 400/100 mg ABT-450/r.

A separate single-dose, open-label, food-effect study dosed 8 healthy adult subjects with ABT-450/r 200/100 mg under fasting and nonfasting conditions in a 2-period, randomized, crossover design.

The protocols were reviewed and approved by an Independent Review Board prior to start of the study. All subjects who participated in a study gave written informed consent prior to starting any study procedures.

Pharmacokinetic Assessments

Complete pharmacokinetic profiles for ABT-450 (and for ritonavir when it was coadministered) were drawn on Day 1 following the morning dose.

ABT-450 and ritonavir concentrations were determined using a liquid chromatography tandem mass spectroscopic method (LCMS/MS) with a lower limit of quantitation of 0.5 ng/mL.

To evaluate the effect of food on the bioavailability of ABT-450 and ritonavir point
estimates and 95% confidence interval for the point estimates were estimated from the analyses of the natural logarithms of Cmax and AUC.

Pharmacokinetic and statistical analysis was conducted using SAS version 9.1 ( Cary, NC).

Safety and Tolerability
Assessments

Safety and tolerability assessments included physical examination, vital sign
measurements and clinical laboratory tests.

12-lead Electrocardiogram (ECG) were recorded in triplicate at multiple time-points before and after dosing. Twelve lead continuous cardiac monitoring was also conducted on all subjects on Day -1 and 1.

Adverse events were monitored throughout the study.

Adverse events were coded using the Medical Dictionary for Regulatory Activities (MedDRA 11.1).


RESULTS

Table 1. Demographic Summary for all Subjects Dosed with
ABT-450, ABT-450/r and Placebo


Pharmacokinetic Results

Pharmacokinetic parameters of ABT-450 following dosing with and without ritonavir are shown in Table 2.


Pharmacokinetics of ABT-450 without Ritonavir

Figure 1 displays the average concentration time profiles for ABT-450.

Increasing the ABT-450 dose from 300 mg to 900 mg increased the Cmax and AUC of ABT-450 in a greater than dose-proportional manner.

Mean terminal half-life (t1/2) was approximately 3 hours for all three dose groups and did not change significantly with dose.

Figure 1. Mean + SD ABT-450 Plasma Concentration–Time Profiles after Single Oral Doses of 300 to 900 mg ABT-450 Without Ritonavir


Table 2. Mean ± SD Pharmacokinetic Parameters of ABT -450
Following Single Escalating Oral Doses of ABT-450 with and
without Ritonavir

‡. Presented as the harmonic mean and pseudo standard deviation.


Pharmacokinetics of 300 mg ABT-450 with and without 100 mg
Ritonavir

The mean plasma concentration time profile of ABT-450 at a dose of 300 mg given without ritonavir and with ritonavir 100 mg are shown in Figure 2.

Mean Cmax and AUC for ABT-450 co-administered with ritonavir increased by approximately 28 and 48-fold, respectively, as compared to ABT-450 300 mg dosed alone.

Mean t1/2 of ABT-450 increased from 3 to 5 hours when coadministered with ritonavir.

Figure 2. Mean + SD ABT-450 Plasma Concentration-Time Profiles Following Single Doses of ABT-450 300 mg without Ritonavir and with Ritonavir 100 mg in Healthy Subjects


Pharmacokinetics of different doses of ABT-450 administered
with 100 mg ritonavir

The effect of ritonavir on increasing doses of ABT-450 was evaluated by dosing ritonavir 100 mg with ABT-450 25 to 400 mg.

The mean plasma concentration time profiles of ABT-450 25 to 400 mg dosed with ritonavir 100 mg are presented in Figure 3.

Consistent with the nonlinearity observed in the Cmax and AUC of ABT-450 alone, the pharmacokinetics of ABT-450 with ritonavir increased in a similar non-proportional manner.

Increasing ABT-450 dose from 25 to 400 mg in the presence of ritonavir 100 mg increased the mean dose normalized Cmax and AUC values by ~ 50 to 60 fold.

Figure 3. Mean + SD ABT-450 Concentration Time Profiles
Following Single Doses of ABT-450 25 to 400 mg with Ritonavir 100 mg in Healthy Subjects


Effect of ABT-450 on Ritonavir Pharmacokinetics

The effect of ABT-450 on ritonavir pharmacokinetics are summarized in Figure 4 and Table 3.

Mean ritonavir Cmax and AUC values appear to increase with increase in ABT-450 exposure.

Apparent differences between the ritonavir pharmacokinetic parameters (with ABT-450 25, 100, 300, and 400 mg) may be attributed to possible effect of ABT-450 on ritonavir and inter-individual variability across groups.

Figure 4. Mean + SD Ritonavir Concentration Time Profiles
Following Single Doses of 100 mg Ritonavir with ABT-450 25 to 400 mg in Healthy Subjects


Table 3. Mean (%CV) Pharmacokinetic Parameters of Ritonavir
Following Single Escalating Oral Doses of ABT-450 with Ritonavir

‡ Presented as the harmonic mean and pseudo standard deviation


Effect of Food on ABT-450 and Ritonavir Pharmacokinetics

Figure 5 displays the average concentration time profiles for ABT-450 and ritonavir following administration of ABT-450/r 200/100 mg under fasting and nonfasting conditions.

The effect of food on ABT-450 pharmacokinetics appears to beminimal as the average ABT-450 Cmax, and AUC were 11 to 19% higher under non-fasting conditions compared to fasting.

Figure 5. Mean ABT-450 and Ritonavir Plasma Concentration-
Time Profiles


Safety Results

ABT-450 with and without ritonavir was generally safe and well tolerated following single oral doses.

Adverse events were all mild in severity and laboratory abnormalities mostly Grade 1.

Only 3/65 healthy volunteers receiving ABT-450 experienced study drug-related adverse events: lower abdominal pain, diarrhea, conjuctival hyperemia and eye pruritus. All events resolved by the end of the study follow-up period.

Transient increases in indirect bilirubin, with no associated effect on direct bilirubin or liver transaminases were observed in 7/12 subjects who received the highest doses of ABT-450/r and achieved ABT-450 concentrations 50-100 fold greater than predicted efficacious exposures. These asymptomatic elevations in indirect bilirubin returned to normal levels within approximately 2 days. No other changes in laboratory values were observed.

There were no clinically significant changes from baseline in vital signs or ECGs

There were no serious adverse events or discontinuations in this study.


Reference

1. Bernstein B, et al. Pharmacokinetics, Safety and Tolerability of the HCV Protease Inhibitor ABT-450 with Ritonavir Following Multiple Ascending Doses in Healthy Adult Volunteers. Annual Meeting of HepDART 2009; Poster 58.