A phase I and pharmacokinetic study of intravenous vinzolidine

Abstract

The semi-synthetic vinca alkaloid vinzolidine was administered to advanced cancer patients as an intravenous bolus on a three day schedule every 21 days. Forty-two patients were treated in this phase I trial. Five partial remissions (breast-l, melanoma-2, renal cancer-2) were seen in 30 evaluable patients. The dose limiting toxicities were myelosuppression and neuropathy. Erratic myelosuppression from course to course within the same patient as seen in previous trials with oral vinzolidine, was not observed with the intravenous formulation. The measured pharmacokinetic parameters conformed best to a 2-compartment model with a mean terminal half-life of 23 hours. The anti-tumor activity observed during this phase I trial and acceptable toxicity provide the basis for initiating phase II studies in selected forms of cancer.

Phase I trial of intravenous vinzolidine (LY 104208) given on a biweekly dosing schedule

“…Although the magnitude of leukopenia was greater at higher doses of VZL, individual patients treated at doses above 5.0 mg/m 2 demonstrated this toxicity after the first treatment, only on repetitive treatments, or not at all. This wide interpatient variation in hematotoxicity was also noted when this drug was given on a day 1-3 schedule every 21 days [9]. Toxic effects, both hematologic and gastrointestinal, led the MTD determined by this study to be 9.0 mg/m 2 which is considerably below the predicted MTD of 15 mg/m 2 and the actual MTD (12.0 mg/m 2) of the day 1-3 phase I intravenous trial of VZL [9].…”

“…This wide interpatient variation in hematotoxicity was also noted when this drug was given on a day 1-3 schedule every 21 days [9]. Toxic effects, both hematologic and gastrointestinal, led the MTD determined by this study to be 9.0 mg/m 2 which is considerably below the predicted MTD of 15 mg/m 2 and the actual MTD (12.0 mg/m 2) of the day 1-3 phase I intravenous trial of VZL [9]. The reasons for this disparity remain unclear but may include incomplete recovery from the toxic effects of treatment at day 15 leading to enhancement of toxicity on subsequent treatment, an effect of the peak level of VZL on organ function, and changes in the pharmacokinetics at higher peak dose levels.…”

Role of pharmacokinetic modeling and simulation in precision dosing of anticancer drugs

“…Malignant cancer Bayesian pop-PK Dose, Evaluation/validation (van Rijswijk et al, 1992) Prostate cancer Bayesian pop-PK Dose, Evaluation/validation (Jodrell et al, 1994) Tamoxifen Cancer (N/S) PK/PD Efficacy, Dose (Gardner, 2002) (Montazeri et al, 2000) Refractory solid tumors Pop-PK/PD Toxicity, Pediatrics (Zamboni et al, 2001) Renal impairment, Ethnicity, Covariates (Lu et al, 2014b) HER2-positive metastatic breast cancer Semi-mech. Pop-PK Covariates (Chudasama et al, 2012) HER2-positive locally Pop-PK Ethnicity (Li et al, 2016) 28 Pharmacokinetic models for precision dosing in oncology -Supplementary appendix (Moore et al, 2011) Acute lymphoblastic leukemia PK Pediatrics (de Graaf et al, 1995) Acute lymphoblastic leukemia, non-Hodgkin lymphoma, Wilms' tumor Bayesian pop-PK Pediatrics, Limited sampling (Gidding et al, 1999) Lympholytic leukemia, histocytic lymphoma, multiple myeloma, idiopathic thrombocytopenic purpura, lymphoma, Hodgkin's disease PK Investigational (Sethi et al, 1981) 29 Pharmacokinetic models for precision dosing in oncology -Supplementary appendix (Puozzo and Gridelli, 2004) Advanced metastatic cancer Bayesian pop-PK Other special populations (elderly) (Gauvin et al, 2000) Non-small cell lung cancer Bayesian pop-PK Dose (Sabot et al, 1998) Advanced metastatic cancer (Taylor et al, 1990) Footnotes: AAG: α1-acid glycoprotein; BMI: body mass index; BSA: body surface area; BW: bodyweight; CLCR: creatinine clearance; CNS: central nervous system; DDIs: drug-drug interactions; eGFR: estimated glomerular filtration rate; GFR: glomerular filtration rate; IBW: ideal bodyweight; N/A: not applicable; N/S: not stated; PBPK: physiologically-based pharmacokinetics; PD: pharmacodynamic; PK: pharmacokinetic; pop: population; SCR: serum creatinine; w.: with.…”