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The purpose of this study is to characterize the population pharmacokinetics (popPK) of subcutaneous (SC) daratumumab in combination with bortezomib, cyclophosphamide, and dexamethasone and explore the relationship between daratumumab systemic exposure and selected efficacy and safety end points in patients with newly diagnosed systemic amyloid light-chain amyloidosis. The popPK analysis included pharmacokinetic and immunogenicity data from patients receiving daratumumab SC in combination with bortezomib, cyclophosphamide, and dexamethasone in the ANDROMEDA study (AMY3001; safety run-in, n = 28; randomized phase, n = 183). Nonlinear mixed-effects modeling was used to characterize the popPK and quantify the impact of potential covariates. The exposure-response (E-R) analysis included data from all patients in the randomized phase of ANDROMEDA (n = 388). Logistic regression and survival analysis were used to evaluate the relationships between daratumumab systemic exposure and efficacy end points. The E-R analysis on safety was conducted using quartile comparison and logistic regression analysis. The observed concentration-time data of daratumumab SC were well described by a 1-compartment popPK model with first-order absorption and parallel linear and nonlinear Michaelis-Menten elimination pathways. None of the investigated covariates were determined to be clinically meaningful. Daratumumab systemic exposure was generally similar across subgroups that achieved different levels of hematologic response, and there was no apparent relationship between daratumumab systemic exposure and the investigated safety end points. In conclusion, the popPK and E-R analyses supported the selected 1800-mg flat dose of daratumumab SC in combination with the bortezomib, cyclophosphamide, and dexamethasone regimen for the treatment of light-chain amyloidosis. No dose adjustment was recommended for investigated covariates., (© 2021, The American College of Clinical Pharmacology.)

In this investigation, the measurement and identification of the S-oxidation products of three simple sulphides-ethyl methyl sulphide (EMS), 4-chlorophenyl methyl sulphide (CPMS) and diphenyl sulphide (DPS)-in rat urine were carried out and a study of the effects of phenobarbitone (PB), beta-naphtho flavone (betaNF) and methimazole on the urinary levels of their metabolites was conducted. Male Wistar rats (n = 4) were pretreated with PB (80 mg/kg/day in saline, i.p.), betaNF (100 mg/kg/day in corn oil, i.p.), methimazole (50 mg/kg/day in saline, i.p.) or the vehicles alone (1 mL/kg) for three consecutive days. After pretreatment, EMS, CPMS or DPS (50 mg/kg in corn oil, 500 microL) was administered orally to the appropriate groups of rats. The animals were placed in metabolic cages and urine samples collected at 24 h intervals over 96 h. Chromatographic and spectroscopic techniques were used for the measurement and identification of the sulphoxides and sulphones of EMS, CPMS and DPS in rat urine. Although only a trace of ethyl methyl sulphoxide (EMSO) was present in rat urine after administration of EMS, ethyl methyl sulphone (EMSO(2)) accounted for about 16% of the administered dose in the urine of male rats given EMS. In addition, pretreatment of rats with methimazole significantly decreased the S-oxidation of EMS. 4-Chlorophenyl methyl sulphone (CPMSO(2)) was the main metabolite recovered in the urine of male rats treated with CPMS, accounting for about 10% of the dose. Pretreatment of rats with PB before administration of CPMS significantly increased the levels of CPMSO(2) excreted in the urine. Additionally, pretreatment of rats with methimazole significantly decreased the S-oxidation of CPMS in vivo. About 2.5% of diphenyl sulphoxide (DPSO) and 4% of diphenyl sulphone (DPSO(2)) were recovered in the urine of male rats given DPS. Pretreatment of rats with PB, betaNF or methimazole before administration of DPS decreased the levels of DPSO and DPSO(2) excreted in the urine, although this was not statistically significant. These results indicate that microsomal monooxygenases mediate the S-oxidation of EMS, CPMS and DPS to their corresponding sulphones via a transient sulphoxide in rats.