Limitations of S-warfarin truncated area under the concentration-time curve to predict cytochrome P450 2c9 activity.

OBJECTIVE: Phenotyping cytochrome P450 (CYP) 2C9 activity with S-warfarin requires extensive blood sampling to characterize area under the concentration-time curve (AUC). This retrospective data analysis was conducted to determine if truncated S-warfarin AUCs can be used to measure CYP2C9 activity. METHODS: S-warfarin plasma concentrations were obtained from healthy adults (n = 84) genotyped as CYP2C9 extensive metabolizers (EMs) from 6 published studies. Subjects received a single 10 mg oral warfarin dose during baseline and treatment conditions. AUC zero to infinity (AUCINF) and truncated AUCs at 48 h (AUC(48)), at 72 h (AUC(72)) and at 96 h (AUC(96)) were determined by noncompartmental analysis. Equivalence was determined via least squares geometric mean ratios (LS-GMRs) with 90% confidence intervals (CI) within 0.8-1.25. RESULTS: A lack of equivalence was observed for AUC(48) and AUC(72) compared to AUC(INF) during baseline conditions in all evaluated studies and during treatment conditions in 5 of 6 studies. Equivalence was observed for AUC(96) compared to AUC(INF) during all baseline and treatment conditions. Results were consistent across all evaluated AUCs between baseline and treatment without a CYP2C9-mediated drug-drug interaction and during induction with an oral contraceptive. During inhibition with fluvastatin, a lack of equivalence was observed with AUC(INF)(LS-GMR [90%CI] = 1.25 [1.16-1.34]) and AUC(96) (1.2 [1.13=1.27]). In contrast, equivalence was observed for AUC(48)(1.15 [1.08-1.22]) and AUC(72) (1.18 [1.11-1.24]). CONCLUSIONS: S-warfarin truncated AUC(48) and AUC(72) poorly characterize AUC(INF) and are unable to detect weak CYP2C9 inhibition with fluvastatin. S-warfarin phenotyping parameters need to ensure blood sampling of at least 96 h to characterize AUC and thus CYP2C9 activity.

Omeprazole limited sampling strategies to predict area under the concentration-time curve ratios: implications for cytochrome P450 2C19 and 3A phenotyping.

PURPOSE: To develop a limited sampling strategy (LSS) to predict area under the concentration-time curve (AUC) ratios of omeprazole (AUC(OPZ)) to its metabolites 5-hydroxyomeprazole (AUC(5OH)) and omeprazole sulfone (AUC(SUL)) as phenotyping parameters for cytochrome P450 (CYP) 2C19 and 3A. METHODS: Data were obtained from 37 (4 women) Caucasian, Chinese, and Korean healthy adults from three published studies. The AUC(OPZ), AUC(5OH), and AUC(SUL) were calculated via noncompartmental analysis. Observed AUC(OPZ, OBS)/AUC(5OH, OBS) and AUC(OPZ, OBS)/AUC(SUL, OBS) were determined. Plasma concentrations of omeprazole, 5-hydroxyomeprazole, and omeprazole sulfone at 1, 1.5, 2, 3, 4, 6, and 8 h post-dose were used to generate limited sampling strategy (LSS) models to predict AUC(OPZ,PRE)/AUC(5OH,PRE) and AUC(OPZ,PRE/)AUC(SUL,PRE). Bias and precision were assessed via percentage mean prediction error (%MPE) and percentage mean absolute error (%MAE), with acceptable limits being <15%. RESULTS: For CYP2C19, the AUC(OPZ,OBS)/AUC(5OH,OBS) was [mean ± standard deviation (SD)] 2.10 ± 1.63. Five LSS models of AUC(OPZ,PRE)/AUC(5OH,PRE) were generated, but none met the bias or precision criteria. Upon stratification by CYP2C19 genotype and ethnicity, a three-timepoint (at 1, 2, and 4 h) LSS model accurately predicted AUC(OPZ)/AUC(5OH) in Caucasian CYP2C19*1/*1 subjects. For CYP3A, AUC(OPZ,OBS)/AUC(SUL,OBS) (mean ± SD) was 1.79 ± 0.67. All LSS models had unacceptable %MAE, even when stratified by CYP2C19 genotype and ethnicity. CONCLUSIONS: A LSS model to predict AUC(OPZ)/AUC(5OH), and thus CYP2C19 activity, was generated for Caucasian CYP2C19*1/*1 subjects. However, additional model validation is needed prior to general use. LSS models to predict AUC(OPZ)/AUC(SUL), and thus CYP3A activity, were not possible, even upon stratification by CYP2C19 genotype and ethnicity.

Evaluation of current and upcoming therapies in oral mucositis prevention.

Cancer chemotherapy has evolved from a few therapeutic agents in three drug classes to more than 50 drugs in over ten drug classes. With generally cytotoxic mechanisms of action, there is continued research interest in preventing and managing adverse events of chemotherapy. Although treatment-induced symptom management has made significant progress, most therapies lead to intolerable reactions that result in a dose reduction or discontinuation of therapy. Mucositis is a common adverse event that can occur after administration of systemic chemotherapy and/or radiation therapy leading to inflammatory lesions anywhere from the oral cavity to the GI tract. Although pathophysiologically similar, gastrointestinal mucositis and oral mucositis (OM) differ in terms of symptom presentation and offending therapies. The focus of the article will be on OM; gastrointestinal mucositis will be mentioned when therapy efficacy is relevant to OM. OM prophylaxis has been a subject of interest for at least the past 30 years, yet progress has been limited due to a lack of understanding of the condition. With the recent introduction of palifermin (Kepivance™), novel therapies continue to be developed that may significantly reduce the incidence, duration and/or severity of OM. In addition, outcomes including an improvement in patient quality of life, increasing treatment dose intensity or reducing healthcare costs may result from successful management of OM prophylaxis. This article will review currently available OM prophylactic therapies. Agents in preclinical or clinical development and natural supplements will also be discussed.