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Limited information is available concerning infant exposure and safety when breastfed by mothers receiving chemotherapy. Whereas defining distribution to breast milk is important to infer drug exposure, infant pharmacokinetics also determine to what extent the infant will be exposed to potential toxic effects. We aimed to assess the impact of chemotherapy containing breast milk on infants by predicting systemic and local (intestinal) exposure of paclitaxel and doxorubicin in infants through breast milk using a physiologically‐based pharmacokinetic (PBPK) approach. Whole‐body PBPK models of i.v. paclitaxel and doxorubicin were extended from the literature, with an oral absorption component to enable predictions in infants receiving paclitaxel or doxorubicin‐containing breast milk. For safety considerations, worst‐case scenarios were explored. Finally, paclitaxel and doxorubicin exposures in plasma and intestinal tissue of infants following feeding of breast milk from paclitaxel‐ or doxorubicin‐treated mothers were simulated and breast milk discarding strategies were evaluated. The upper 95th percentile of the predicted peak concentrations in peripheral venous blood were 3.48 and 0.74 nM (0.4%–1.7% and 0.1%–1.8% of on‐treatment) for paclitaxel and doxorubicin, respectively. Intestinal exposure reached peak concentrations of 1.0 and 140 μM for paclitaxel and doxorubicin, respectively. Discarding breast milk for the first 3 days after maternal chemotherapy administration reduced systemic and tissue exposures even further, to over 90% and 80% for paclitaxel and doxorubicin, respectively. PBPK simulations of chemotherapy exposure in infants after breastfeeding with chemotherapy containing breast milk suggest that particularly local gastrointestinal adverse events should be monitored, whereas systemic adverse events are not expected. [ABSTRACT FROM AUTHOR]

ModraPac001 (MP1) and ModraPac005 (MP5) are novel oral paclitaxel formulations that are coadministered with the cytochrome P450 3A4 inhibitor ritonavir (r), enabling daily low‐dose metronomic (LDM) treatment. The primary aim of this study was to determine the safety, pharmacokinetics and maximum tolerated dose (MTD) of MP1/r and MP5/r. The second aim was to establish the recommended phase 2 dose (RP2D) as LDM treatment. This was an open‐label phase 1 trial. Patients with advanced solid tumors were enrolled according to a classical 3+3 design. After initial employment of the MP1 capsule, the MP5 tablet was introduced. Safety was assessed using the Common Terminology Criteria for Adverse Events version 4.02. Pharmacokinetic sampling was performed on days 1, 2, 8, and 22 for determination of paclitaxel and ritonavir plasma concentrations. In this study, 37 patients were treated with up to twice‐daily 30‐mg paclitaxel combined with twice‐daily 100‐mg ritonavir (MP5/r 30‐30/100‐100) in 9 dose levels. Dose‐limiting toxicities were nausea, (febrile) neutropenia, dehydration and vomiting. At the MTD/RP2D of MP5/r 20‐20/100‐100, the maximum paclitaxel plasma concentration and area under the concentration‐time curve until 24 hours were 34.6 ng/mL (coefficient of variation, 79%) and 255 ng • h/mL (coefficient of variation, 62%), respectively. Stable disease was observed as best response in 15 of 31 evaluable patients. Based on these results, LDM therapy with oral paclitaxel coadministrated with ritonavir was considered feasible and safe. The MTD and RP2D were determined as MP5/r 20‐20/100‐100. Further clinical development of MP5/r as an LDM concept, including potential combination treatment, is warranted. [ABSTRACT FROM AUTHOR]

First-in-human dose predictions are primarily based on no-observed-adverse-effect levels in animal studies. Predictions from these animal models are only as effective as their ability to predict human results. To narrow the gap between human and animals, researchers have, among other things, focused on the replacement of animal cytochrome P450 (CYP) enzymes with their human counterparts (called humanization), especially in mice. Whereas research in humanized mice is extensive, the emphasis has been particularly on qualitative rather than quantitative predictions. Because the CYP3A4 enzyme is most involved in the metabolism of clinically used drugs, most benefit was expected from CYP3A4 models. There are several applications of these mouse models regarding in vivo CYP3A4 functionality, one of which might be their capacity to help improve first-in-human (FIH) dose predictions for CYP3A4-metabolized drugs. To evaluate whether human-CYP3A4-transgenic mouse models are better predictors of human exposure compared to the wild-type mouse model, we performed a meta-analysis comparing both mouse models in their ability to accurately predict human exposure of small-molecule drugs metabolized by CYP3A4. Results showed that, in general, the human-CYP3A4-transgenic mouse model had similar accuracy in the prediction of human exposure compared to the wild-type mouse model, suggesting that there is limited added value in humanization of the mouse Cyp3a enzymes if the primary aim is to acquire more accurate FIH dose predictions. Despite the results of this meta-analysis, corrections for interspecies differences through extension of human-CYP3A4-transgenic mouse models with pharmacokinetic modeling approaches seems a promising contribution to more accurate quantitative predictions of human pharmacokinetics., (© 2023 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

ModraPac001 (MP1) and ModraPac005 (MP5) are novel oral paclitaxel formulations that are coadministered with the cytochrome P450 3A4 inhibitor ritonavir (r), enabling daily low-dose metronomic (LDM) treatment. The primary aim of this study was to determine the safety, pharmacokinetics and maximum tolerated dose (MTD) of MP1/r and MP5/r. The second aim was to establish the recommended phase 2 dose (RP2D) as LDM treatment. This was an open-label phase 1 trial. Patients with advanced solid tumors were enrolled according to a classical 3+3 design. After initial employment of the MP1 capsule, the MP5 tablet was introduced. Safety was assessed using the Common Terminology Criteria for Adverse Events version 4.02. Pharmacokinetic sampling was performed on days 1, 2, 8, and 22 for determination of paclitaxel and ritonavir plasma concentrations. In this study, 37 patients were treated with up to twice-daily 30-mg paclitaxel combined with twice-daily 100-mg ritonavir (MP5/r 30-30/100-100) in 9 dose levels. Dose-limiting toxicities were nausea, (febrile) neutropenia, dehydration and vomiting. At the MTD/RP2D of MP5/r 20-20/100-100, the maximum paclitaxel plasma concentration and area under the concentration-time curve until 24 hours were 34.6 ng/mL (coefficient of variation, 79%) and 255 ng • h/mL (coefficient of variation, 62%), respectively. Stable disease was observed as best response in 15 of 31 evaluable patients. Based on these results, LDM therapy with oral paclitaxel coadministrated with ritonavir was considered feasible and safe. The MTD and RP2D were determined as MP5/r 20-20/100-100. Further clinical development of MP5/r as an LDM concept, including potential combination treatment, is warranted., (© 2020, The American College of Clinical Pharmacology.)