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Aim: A population pharmacokinetic (PPK) model was developed to characterize pharmacokinetics (PK) of subcutaneous or intravenous daratumumab administration in a new indication (i.e., combination with pomalidomide and dexamethasone [D‐Pd] in patients with relapsed or refractory multiple myeloma [RRMM]). Analyses were conducted to explore exposure–response (E‐R) relationships for efficacy and select treatment‐emergent adverse events (TEAEs). Methods: The PPK analysis included pooled data from the D‐Pd cohorts of the phase 3 APOLLO and phase 1b EQUULEUS studies. Covariates were evaluated in the PPK model. Model‐predicted exposures to daratumumab were compared between covariate subgroups of interest and used to investigate relationships between daratumumab exposure and efficacy and safety in APOLLO. Results: The PPK analysis included 1146 daratumumab PK samples from 239 patients (APOLLO, n = 140; EQUULEUS, n = 99). Observed concentration–time data of daratumumab were well described by a two‐compartment PPK model with first‐order absorption and parallel linear and nonlinear elimination pathways. Treatment with D‐Pd provided similar daratumumab PK characteristics versus historical daratumumab monotherapy. The E‐R dataset contained data from 290 APOLLO patients (D‐Pd, n = 140; Pd, n = 150). The PK–efficacy relationship of daratumumab supported improved progression‐free survival for patients in the D‐Pd group vs. the Pd group. Additionally, TEAEs did not increase with increasing PK exposure in the D‐Pd group. Conclusions: The PPK and E‐R analyses support the daratumumab subcutaneous 1800 mg dosing regimen in combination with Pd for treatment of patients with RRMM. No dose adjustment is recommended in this indication for any of the investigated factors, none of which had clinically relevant effects on daratumumab PK. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Aims To assess the safety, tolerability, pharmacokinetics ( PK), pharmacodynamics (PD) and immunogenicity of CNTO 5825 following single-dose intravenous (i.v.) and subcutaneous (s.c.) administration in healthy and healthy atopic subjects. Methods Sixty-four subjects received a single dose of placebo or CNTO 5825 (0.1, 0.3, 1.0, 3.0, or 10 mg kg−1 i.v. in a dose-escalating manner, or 3.0 mg kg−1 s.c. in healthy subjects; and 10 mg kg−1 i.v. in healthy atopic subjects). Subjects were observed for 96 h postadministration and followed for 16 weeks. Safety and tolerability were monitored, and serum samples were collected to measure CNTO 5825 concentrations, antibodies to CNTO 5825 and PD biomarkers. Results Most adverse events were mild to moderate in severity and considered to be unrelated to CNTO 5825, with no dose-dependent trends seen. The two serious adverse events were considered to be unrelated to CNTO 5825. After i.v. administration, CNTO 5825 exhibited linear PK, with a terminal half-life of ∼22-32 days. After a single 3 mg kg−1 s.c. dose in healthy subjects, CNTO 5825 was absorbed into the systemic circulation with a median time to maximum serum concentration (tmax) of 5.45 days and absolute bioavailability of ∼75%. The PK profile of CNTO 5825 at 10 mg kg−1 was similar in both healthy and healthy atopic subjects. No antibodies to CNTO 5825 were detected through week 16. In the CNTO 5825-treated healthy atopic subjects, there was a significant reduction in serum IgE and C-C motif chemokine ligand 17 ( P = 0.028 and 0.068 vs. placebo, respectively). Conclusions CNTO 5825 was well tolerated, had an acceptable safety profile, exhibited linear PK characteristics, and no detected antibodies to CNTO 5825. [ABSTRACT FROM AUTHOR]

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), β-naphthoflavone ( βNF) 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.), βNF (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 µL) 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 (EMSO2) 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 (CPMSO2) 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 CPMSO2 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 (DPSO2) were recovered in the urine of male rats given DPS. Pretreatment of rats with PB, βNF or methimazole before administration of DPS decreased the levels of DPSO and DPSO2 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. Copyright © 2004 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

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.