Volumetric absorptive microsampling-LC-MS/MS assays for quantitation of giredestrant in dried human whole blood.

Volumetric absorption microsampling devices offer minimally invasive and user-friendly collection of capillary blood in volumes as low as 10 µl. Herein we describe the assay validation for determination of the selective estrogen receptor degrader giredestrant (GDC-9545) in dried human whole blood collected using the Mitra® and Tasso-M20 devices. Both LC-MS/MS assays met validation acceptance criteria for the linear range 1-1000 ng/ml giredestrant. Mitra and Tasso-M20 samples were stable for 84 and 28 days at ambient conditions, respectively, and for 7-9 days at 40 and -70°C. Blood hematocrit, hyperlipidemia and anticoagulant did not impact quantitation of giredestrant. These validated assays are suitable for the determination of giredestrant in dried blood samples collected using Mitra and Tasso-M20 microsampling devices.

Evaluation of Potential Drug-Drug Interaction Between Delayed-Release Dimethyl Fumarate and a Commonly Used Oral Contraceptive (Norgestimate/Ethinyl Estradiol) in Healthy Women.

Delayed-release dimethyl fumarate (DMF) is an oral therapy for relapsing multiple sclerosis with anti-inflammatory and neuroprotective properties. This 2-period crossover study was conducted to evaluate the potential for drug-drug interaction between DMF (240 mg twice daily) and a combined oral contraceptive (OC; norgestimate 250 µg, ethinyl estradiol 35 µg). Forty-six healthy women were enrolled; 32 completed the study. After the lead-in period (OC alone), 41 eligible participants were randomized 1:1 to sequence 1 (OC and DMF coadministration in period 1; OC alone in period 2) or sequence 2 (regimens reversed). Mean concentration profiles of plasma norelgestromin (primary metabolite of norgestimate) and ethinyl estradiol were superimposable following OC alone and OC coadministered with DMF, with 90% confidence intervals of geometric mean ratios for area under the plasma concentration-time curve over the dosing interval and peak plasma concentration contained within the 0.8-1.25 range. Low serum progesterone levels during combined treatment confirmed suppression of ovulation. The pharmacokinetics of DMF (measured via its primary active metabolite, monomethyl fumarate) were consistent with historical data when DMF was administered alone. No new safety concerns were identified. These results suggest that norgestimate/ethinyl estradiol-based OCs may be used with DMF without dose modification.