1054 Safety, Pharmacokinetics and Antiviral Effect of Bi 207127, a Novel HCV Rna Polymerase Inhibitor, After 5 Days Oral Treatment in Patients With Chronic Hepatitis C

Erhardt, A.; Wedemeyer, Heiner; Benhamou, Yves; Moellekens, C.; Forns, Xavier; Pol, S.; Calleja, J.L.; Ross, Sheila K.; Spangenberg, Hans Christian; García‐Samaniego, J.; Fuchs, Margit; Enriquez, J.; Wiegand, Timothy J.; Stern, Jerry O.; Wu, Kuan-Han Hank; Nehmiz, Gerhard; Steffgen, Jürgen

doi:10.1016/s0168-8278(09)61056-4

Cited by 23 publications

(18 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As shown in Fig. 2A, the retrospective PK-PD data analysis based on shortterm monotherapy data from four Boehringer Ingelheim HCV antivirals, two NS3 proteases (BILN 2061 and faldaprevir), and two nonnucleoside NS5B polymerase inhibitors (BILB 1941 and BI 207127) (11,16,20,22,26) led to a poor correlation (r 2 ) of 0.48 for the IQ-maximum viral load reduction (VLR) relationship analysis and a corresponding 50% effective dose (ED 50 ) IQ of 42, with a large 95% confidence interval (CI), 0.1 to 148534. Exploration of the IQ-VLR relationship analysis using both maximum concentration of drug in plasma (C max ) and AUC exposures failed to improve that relationship compared to the analysis using C min .…”

Section: Resultsmentioning

confidence: 99%

“…To minimize variability of other factors such as the emergence of resistance, the PK-PD relationship analysis for all four in-house DAAs tested in the clinic were based on the mean plasma C min and the mean maximum viral load reduction obtained following a short monotherapy, 2 to 5 days (11,16,20,22,26). All research using human subjects cited in these references used study protocols which where VLR refers to the mean maximum viral load reduction in log scale, X refers to the values of IQ or LCIQ, and 50% effective dose (ED 50 ) here refers to the IQ or LCIQ that corresponds to the 50% maximum VLR on the log scale.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

The Liver Partition Coefficient-Corrected Inhibitory Quotient and the Pharmacokinetic-Pharmacodynamic Relationship of Directly Acting Anti-Hepatitis C Virus Agents in Humans

Duan

Bolger

Garneau

et al. 2012

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Pharmacokinetic-pharmacodynamic (PK-PD) data analyses from early hepatitis C virus (HCV) clinical trials failed to show a good correlation between the plasma inhibitory quotient (IQ) and antiviral activity of different classes of directly acting antiviral agents (DAAs). The present study explored whether use of the liver partition coefficient-corrected IQ (LCIQ) could improve the PK-PD relationship. Animal liver partition coefficients (Kp liver ) were calculated from liver to plasma exposure ratios. In vitro hepatocyte partition coefficients (Kp hep ) were determined by the ratio of cellular to medium drug concentrations. Human Kp liver was predicted using an in vitro-in vivo proportionality method: the species-averaged animal Kp liver multiplied by the ratio of human Kp hep over those in animals. LCIQ was calculated using the IQ multiplied by the predicted human T he inhibitory quotient (IQ) is a common pharmacological predictor of antiviral activity and generally represents the ratio between the trough plasma concentration (C min ) and an in vitro potency parameter such as 50% effective concentration (EC 50 ) (3). Several modifications have been proposed to improve the prognostic value of the plasma IQ-antiviral response relationship, including the use of serum-shifted EC 50 s, the consideration of intracellular drug concentrations, and the potential complication related to drug resistance mutations (1, 3), as well as the proposed instantaneous IQ model, which suggested that the slope of the dose-response curve is another critical fact to consider (34). Recently, several directly acting antivirals (DAAs) targeting HCV have been advanced into clinical trials, and the first DAAs have now been approved for use in combination therapy with pegylated interferon and ribavirin (2,18,21,32,35). The first DAA tested in chronic hepatitis C virus (HCV)-infected patients with potent antiviral effect was BILN 2061 (16, 20), which showed a clear dosedependent in vivo activity. Even at the low oral twice-daily (b.i.d.) dose of 25 mg, a mean of 2-log 10 IU/ml viral load reduction (VLR) was observed following a brief treatment (2 days) (16). The corresponding mean plasma IQ was 6.6 at this low oral dosage. A similar plasma IQ, but significantly greater antiviral effects, was observed for telaprevir dosed at 750 mg three times a day (t.i.d.), based on published clinical pharmacokinetic (PK) data (33) and the EC 50 s measured under the same experimental condition as used for BILN 2061 from our lab. Clinical trials for the polymerase inhibitor BILB 1941 (11) demonstrated that a mean plasma IQ of 21 was achieved with the t.i.d. oral dose of 300 mg (about 3.5-fold greater than for BILN 2061 at 25 mg b.i.d. or telaprevir at 750 mg t.i.d.). Yet this higher plasma IQ was associated with much lower antiviral effects in the clinic, with a mean viral load reduction of only 1 log 10 IU/ml. Correction of plasma IQ using serum-shifted EC 50 s, or plasma protein binding-corrected IQs, failed to improve the PK-pharmacodynamics (PD) relationshi...

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

The Liver Partition Coefficient-Corrected Inhibitory Quotient and the Pharmacokinetic-Pharmacodynamic Relationship of Directly Acting Anti-Hepatitis C Virus Agents in Humans

Duan

Bolger

Garneau

et al. 2012

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…The second generation of protease inhibitors (PI) should result in compounds with more powerful antiviral activity but unfortunately, with still some level of cross resistance mutations within the class [29][30][31][32][33][34][35][36][37][38][39][40]. The incidence and prevalence of resistance in PIs and the role of potential combination therapies.…”

Section: Introductionmentioning

confidence: 99%

Hepatitis C virus resistance to protease inhibitors

Halfon

Locarnini

2011

Journal of Hepatology

286

241

View full text Add to dashboard Cite

Recent advances in molecular biology have led to the development of novel small molecules that target specific viral proteins of the hepatitis C virus (HCV) life cycle. These drugs, collectively termed directly acting antivirals (DAA) against HCV, include a range of non-structural (NS) 3/NS4A protease, NS5B polymerase, and NS5A inhibitors at various stages of clinical development. The rapid replication rate of HCV, along with the low fidelity of its polymerase, gives rise to generations of mutations throughout the viral genome resulting in remarkable sequence variation in the HCV population, known as a quasispecies. The efficacy of DAAs is limited by the presence of those mutations that give rise to amino-acid substitutions within the targeted protein, and that affect the viral sensitivity to these compounds. Thus, due to the high genetic variability of HCV, variants with reduced susceptibility to DAA can occur naturally even before treatment begins, but usually at low levels. Not surprisingly then, these changes are selected in patients either breaking through or not responding to potent DAA treatment. In vitro or in vivo, six major position mutations in the NS3 HCV protease (36, 54, 155, 156, 168, and 170) have now been reported associated with different levels of resistance. The amino acid composition at several of the drug resistance sites can vary between the HCV genotypes/subtypes, resulting in different consensus amino acids leading to a reduction in replicative fitness as well as reduced DAA sensitivity. Different amino acid diversity profiles for HCV genotypes/subtypes suggest differences in the position/type of immune escape and drug resistance mutations. Also, different pathways of resistance profiles based on the chemical scaffold (linear or macrocyclic) of the protease inhibitors have been described. This review first describes how resistance to a protease inhibitor can develop and then provides an overview of the mechanism of how particular mutations confer varying levels of resistance to protease inhibitor, which have been identified and characterized using both genotypic and phenotypic tools. Future potential therapeutic strategies to assist patients who do develop resistance to protease inhibitors are also outlined. The challenge developing new HCV protease inhibitors should take into consideration not only the antiviral potency of the drugs, the occurrence and importance of side effects, the frequency of oral administration, but also the resistance profiles of these agents.

show abstract

“…Cell-based HCV sub-genomic replicon EC 50 values are 23 and 11 nmol/L for HCV-1a and HCV-1b, respectively (Larrey et al, 2009b). In a double blind, sequential group comparison of HCV-1 subjects with minimal to mild liver fibrosis, treatments of 100-1200 mg BI 207127 TID were administered over 5 d. All subjects were then tested for plasma HCV RNA virus load (VL) using the Roche COBAS TaqMan assay in the following 10-14 d. As compared to mean 6.4 log 10 IU/ml, VL decreased by ≥1 log 10 IU/ml in 2/9, 6/9, 8/9, 8/9 and 10/10 subjects treated with 100, 200, 400, 800, and 1200 mg, respectively.…”

Section: Bi 207127mentioning

confidence: 98%

New developments in small molecular compounds for anti-hepatitis C virus (HCV) therapy

Tong

Wang

2012

J. Zhejiang Univ. Sci. B

View full text Add to dashboard Cite

Abstract:Infection with hepatitis C virus (HCV) affects approximately 170 million people worldwide. However, no vaccine or immunoglobulin is currently available for the prevention of HCV infection. The standard of care (SOC) involving pegylated interferon-α (PEG-IFN α) plus ribavirin (RBV) for 48 weeks results in a sustained virologic response in less than 50% of patients with chronic hepatitis C genotype 1, the most prevalent type of HCV in North America and Europe. Recently, reliable in vitro culture systems have been developed for accelerating antiviral therapy research, and many new specifically targeted antiviral therapies for hepatitis C (STAT-C) and treatment strategies are being evaluated in clinical trials. These new antiviral agents are expected to improve present treatment significantly and may potentially shorten treatment duration. The aim of this review is to summarize the current developments in new anti-HCV drugs.

show abstract

1054 Safety, Pharmacokinetics and Antiviral Effect of Bi 207127, a Novel HCV Rna Polymerase Inhibitor, After 5 Days Oral Treatment in Patients With Chronic Hepatitis C

Cited by 23 publications

References 0 publications

The Liver Partition Coefficient-Corrected Inhibitory Quotient and the Pharmacokinetic-Pharmacodynamic Relationship of Directly Acting Anti-Hepatitis C Virus Agents in Humans

The Liver Partition Coefficient-Corrected Inhibitory Quotient and the Pharmacokinetic-Pharmacodynamic Relationship of Directly Acting Anti-Hepatitis C Virus Agents in Humans

Hepatitis C virus resistance to protease inhibitors

New developments in small molecular compounds for anti-hepatitis C virus (HCV) therapy

Contact Info

Product

Resources

About