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Species difference in paclitaxel disposition correlated with poor pharmacological efficacy translation from mice to humans.

ABSTRACT: Paclitaxel (PTX) products currently approved by the Food and Drug Administration include Kolliphor EL-paclitaxel micelles (KoEL-paclitaxel, Taxol) and nanoparticle albumin-bound paclitaxel (nab-paclitaxel, Abraxane). Despite containing the same cytotoxic agent, different PTX formulations have distinct pharmacological responses and indications in patients with cancer. Several novel PTX delivery vehicles that have shown superior efficacy to Taxol in animal models failed to demonstrate efficacy in Phase II/III human clinical trials. A 10 mg/kg IV dose of KoEL-paclitaxel or nab-paclitaxel was administered to mice, and the pharmacokinetics (PK) profile of PTX in mice was then compared with the human PK profile from clinical studies. Population PK model and simulation was used to delineate the distribution and elimination characteristics in each species. In addition, tumor shrinkage was measured after weekly administration of both formulations in mouse xenograft model. Our pharmacokinetic modeling results suggested that elimination predominates over distribution in driving PTX disposition in mice, hence restricting the PTX tissue accumulation. Moreover, the rapid elimination of PTX in mice minimized the different formulation effects on PTX tissue distribution, which is believed to link to the superior efficacy of nab-paclitaxel over KoEL-paclitaxel seen in human. In contrast to mice, PTX distribution predominates over elimination in human, and the decline in plasma PTX concentration reflected the deeper tissue distribution by nab-paclitaxel. This species difference in PTX distribution and elimination hinders a simple direct extrapolation from animals to humans. Therefore, species difference in drug distribution and elimination should be carefully assessed during translational drug development.

SUBMITTER: Li YF

PROVIDER: S-EPMC6235005 | biostudies-other | 2018

REPOSITORIES: biostudies-other

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Species difference in paclitaxel disposition correlated with poor pharmacological efficacy translation from mice to humans.

Li Ying Fei YF Zhang Chengyue C Zhou Simon S He Miao M Zhang Huixia H Chen Nianhang N Li Feng F Luan Xin X Pai Manjunath M Yuan Hebao H Sun Duxin D Li Yan Y

Clinical pharmacology : advances and applications 20181108

<h4>Background</h4>Paclitaxel (PTX) products currently approved by the Food and Drug Administration include Kolliphor EL-paclitaxel micelles (KoEL-paclitaxel, Taxol) and nanoparticle albumin-bound paclitaxel (<i>nab</i>-paclitaxel, Abraxane). Despite containing the same cytotoxic agent, different PTX formulations have distinct pharmacological responses and indications in patients with cancer. Several novel PTX delivery vehicles that have shown superior efficacy to Taxol in animal models failed t ...[more]

PMID: 30519122

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Project description:PURPOSE:Paclitaxel, ifosfamide, and cisplatin (TIP) achieved complete responses (CRs) in two thirds of patients with advanced germ cell tumors (GCTs) who relapsed after first-line chemotherapy with cisplatin and etoposide with or without bleomycin. We tested the efficacy of first-line TIP in patients with intermediate- or poor-risk disease. PATIENTS AND METHODS:In this prospective, multicenter, single-arm phase II trial, previously untreated patients with International Germ Cell Cancer Collaborative Group poor-risk or modified intermediate-risk GCTs received four cycles of TIP (paclitaxel 240 mg/m(2) over 2 days, ifosfamide 6 g/m(2) over 5 days with mesna support, and cisplatin 100 mg/m(2) over 5 days) once every 3 weeks with granulocyte colony-stimulating factor support. The primary end point was the CR rate. RESULTS:Of the first 41 evaluable patients, 28 (68%) achieved a CR, meeting the primary efficacy end point. After additional accrual on an extension phase, total enrollment was 60 patients, including 40 (67%) with poor risk and 20 (33%) with intermediate risk. Thirty-eight (68%) of 56 evaluable patients achieved a CR and seven (13%) achieved partial responses with negative markers (PR-negative) for a favorable response rate of 80%. Five of seven achieving PR-negative status had seminoma and therefore did not undergo postchemotherapy resection of residual masses. Estimated 3-year progression-free survival and overall survival rates were 72% (poor risk, 63%; intermediate risk, 90%) and 91% (poor risk, 87%; intermediate risk, 100%), respectively. Grade 3 to 4 toxicities consisted primarily of reversible hematologic or electrolyte abnormalities, including neutropenic fever in 18%. CONCLUSION:TIP demonstrated efficacy as first-line therapy for intermediate- and poor-risk GCTs with an acceptable safety profile. Given higher rates of favorable response, progression-free survival, and overall survival compared with prior first-line studies, TIP warrants further study in this population.

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Species difference in paclitaxel disposition correlated with poor pharmacological efficacy translation from mice to humans.

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Species difference in paclitaxel disposition correlated with poor pharmacological efficacy translation from mice to humans.

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