Abstract. We report a population pharmacokinetic (PK) and pharmacodynamic (PD) model of orally administered ribavirin in patients with chronic hepatitis C virus (HCV) infection enrolled in a multicenter clinical trial, including the estimation of covariate effects on ribavirin PK parameters and sustained viral response (SVR). Ribavirin concentrations obtained from 144 patients, consisting of n=71 African American (AA) and n=73 Caucasian Americans (CA), during 24 weeks of therapy were best described by a twocompartment model with first-order absorption and elimination parameterized in terms of apparent oral clearance (CL/F), apparent central volume (Vc/F), apparent peripheral volume (Vp/F), and apparent intercompartmental clearance (Q/F). The typical population parameters were CL/F (19.0 L/h), Vc/F (1,130 L), Vp/F (4,020 L), and Q/F (38.6). The Vp/F was approximately 50% greater in AA compared to CA. Significant covariates in the SVR model included IL-28B genotype, homeostasis model assessment of insulin resistance, and ribavirin exposure during the first week (AUC 0−7 ). The population PK and logistic regression models both described the observed ribavirin concentration data and SVR data well. These findings suggest that optimization of ribavirin plasma concentrations during the first week of ribavirin dosing is most critical in AA patients in order to increase the rate of SVR, especially those with the IL-28B TT genotype.

OBJECTIVES Peginterferon and ribavirin treatment is less effective for hepatitis C virus (HCV) genotype 1 infections in African Americans (AA) compared with Caucasian Americans (CA). Host genetic variability near the interleukin-28B (IL28B) gene locus is partly responsible. We investigated the relationship between ribavirin drug exposure and week 24 and 72 (sustained virologic response, SVR) responses (undetected serum HCV RNA) in 71 AA and 74 CA with HCV genotype 1 who received >90 % of the prescribed peginterferon and weight-based ribavirin (1,000 or 1,200 mg per day) from week 1 to 24. METHODS Ribavirin plasma levels were measured at weeks 1, 2, 4, 8, 12 and 24; ribavirin area under the concentration vs. time curve (AUC) was calculated using the linear trapezoidal rule. RESULTS Compared with CA, AA had lower week 24 (WK24VR) (57.8 vs. 78.1; P < 0.05) and week 72 (SVR) (36.6 % vs 54.8 %; P < 0.05) response rates. AA also had significantly lower ribavirin exposure (AUC) from week 1 to 12 (P < 0.05). Ribavirin exposures ≥ 4,065 and ≥ 4,480 ng/ml/day in the first week (AUC0–7) were thresholds for WK24VR and SVR in receiver-operating characteristic curve analyses. AA were less likely to have a threshold ribavirin AUC0–7 level than CA (P < 0.05). There were no significant racial differences in WK24VR (AA: 77 vs. CA: 84 %) and SVR (AA: 52 vs. CA: 60 %) rates in patients who met the ribavirin AUC0–7 thresholds. Ribavirin AUC0–7 predicted WK24VR and SVR independently of IL28B single-nucleotide polymorphism rs12979860 genotype. Yet, achieving threshold AUC0–7 levels increased response rates primarily in AA with the less favorable non-C/C genotypes. CONCLUSIONS Standard weight-based dosing leads to suboptimal ribavirin exposure in AA and contributes to the racial disparity in peginterferon and ribavirin treatment efficacy for HCV genotype 1.

ABT‐751 is an orally bioavailable sulfonamide with antimitotic properties. A nonrandomized phase 1 dose‐escalation study of ABT‐751 in combination with CAPIRI (capecitabine and irinotecan) and bevacizumab was conducted to define the maximum tolerated dose, dose‐limiting toxicity (DLT), and pharmacokinetics in patients with advanced colorectal cancer. Patients were treated with ABT‐751 daily for 7 days (alone) and then began 21‐day cycles of treatment with ABT‐751 daily and capecitabine twice daily for 14 days plus irinotecan on day 1 intravenously. Bevacizumab was added as standard of care at 7.5 mg/kg on day 1 after the first 2 dose levels. Because of intolerance to the regimen, a reduced dose of ABT‐751 was also explored with reduced‐dose and full‐dose CAPIRI with bevacizumab. ABT‐751 and irinotecan pharmacokinetics, ABT‐751 glucuronidation, and protein binding were explored. Twenty‐four patients were treated over 5 dose levels. The maximum tolerated dose was ABT‐751 125 mg combined with full‐dose CAPIRI and bevacizumab 7.5 mg/kg on day 1. DLTs were hypokalemia, elevated liver tests, and febrile neutropenia. ABT‐751 is metabolized by UGT1A8 and to a lesser extent UGT1A4 and UGT1A1. Irinotecan and APC exposure were increased, SN‐38 exposure was similar, and SN‐38 glucuronide exposure was decreased. Clinically relevant alterations in ABT‐751 and irinotecan pharmacokinetics were not observed. Despite modest efficacy, the combination of ABT‐751, CAPIRI, and bevacizumab will not be studied further in colorectal cancer.

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