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

Abstract

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...

Generating an In Vitro–In Vivo Correlation for Metabolism and Liver Enrichment of a Hepatitis C Virus Drug, Faldaprevir, Using a Rat Hepatocyte Model (HepatoPac)

“…Results from the QWBA study reflect total faldaprevir-related radioactivity and do not (Chen et al, 2014). (Duan et al, 2012a). In contrast, liver enrichment values achieved with rat HepatoPac were consistent with QWBA and in vivo data, ranging from approximately 13-to 51-fold.…”

“…Uptake studies using suspended hepatocytes were performed as previously described (Duan et al, 2012a). In short, reconstituted suspended rat hepatocytes (viability .85%) were incubated in hepatocyte incubation medium in an atmosphere of 5% CO 2 for 10 minutes at 37°C.…”

Distribution of Curcumin and THC in Peripheral Blood Mononuclear Cells Isolated from Healthy Individuals and Patients with Chronic Lymphocytic Leukemia

“…Cell distribution studies. The distribution of curcumin in the form of Lipocurc™ was conducted in 1.5 ml conical microfuge tubes either in replicates of 3, 4 or 6 and was based on the method of Duan et al, (24). The assay volume consisted of 300 μl of human plasma protein supplemented KHIM, 100 μl of cell suspension and 100 μl of plasma protein supplemented KHIM containing Lipocurc™ for a total assay volume of 500 μl, a plasma protein content of 50% v/v and nominal concentration of curcumin of between ~2-3 μM.…”

Distribution and Metabolism of Lipocurc™ (Liposomal Curcumin) in Dog and Human Blood Cells: Species Selectivity and Pharmacokinetic Relevance

“…The distribution of curcumin into hepatocytes was evaluated for comparison with blood cell distribution and metabolism. In order to maintain as physiologic an environment as possible and to limit the hydrolytic degradation of curcumin, the incubation was performed in the presence of 50% plasma, the maximum amount of plasma that could be introduced into a HEPES buffer at pH of 7.4 without changing the pH levels of the medium (28). Identical assay conditions as the ones used in the experiments presented here were used to successfully predict the in vivo distribution of hepatitis C antiviral development candidates (28).…”

“…Cell distribution studies. The distribution of curcumin in the form of Lipocurc™ was conducted in 1.5 ml conical microfuge tubes in triplicate and was based on the method of Duan et al (28). The assay volume consisted of 300 μl of human plasma protein supplemented KHIM, 100 μl of cell suspension and 100 μl of plasma protein supplemented KHIM containing Lipocurc™ for a total assay volume of 500 μl, a plasma protein content of 50% v/v and nominal concentration of curcumin of ~2 μM.…”