Konstanze Diefenbach

Folate status and homocysteine levels during a 24-week oral administration of a folate-containing oral contraceptive: a randomized, double-blind, active-controlled, parallel-group, US-based multicenter study

BACKGROUND This study investigated the effects of adding levomefolate calcium 0.451 mg (the calcium salt of L-5-methyltetrahydrofolate; Metafolin®) to an oral contraceptive containing ethinylestradiol (EE) 20 mcg/drospirenone (drsp) 3 mg on folate levels in healthy women seeking contraception. STUDY DESIGN In this randomized, double-blind, multicenter US-based study, women (18-40 years) received 24 weeks (six cycles) of EE/drsp/levomefolate calcium or EE/drsp for 24 days followed by 4 days of levomefolate calcium alone or placebo, respectively. The primary efficacy variables were red blood cell (RBC) and plasma folate levels at 24 weeks. RESULTS At week 24, increases from baseline in mean RBC (990 ± 390 nmol/L to 1406 ± 440 nmol/L) and plasma folate (45.0 ± 17.6 nmol/L to 60.8 ± 19.9 nmol/L) levels were observed in women who received EE/drsp/levomefolate calcium [per protocol set (n=262); all values are displayed as mean ± standard deviation]. In contrast, marginal fluctuations were observed with EE/drsp (p<.0001 for between-treatment differences at week 24). CONCLUSION Clinically significant increases in folate status were observed with EE/drsp/levomefolate calcium compared with EE/drsp alone in US women of childbearing age.

Pharmacologic activity and pharmacokinetics of metabolites of regorafenib in preclinical models

Regorafenib is an orally administered inhibitor of protein kinases involved in tumor angiogenesis, oncogenesis, and maintenance of the tumor microenvironment. Phase III studies showed that regorafenib has efficacy in patients with advanced gastrointestinal stromal tumors or treatment‐refractory metastatic colorectal cancer. In clinical studies, steady‐state exposure to the M‐2 and M‐5 metabolites of regorafenib was similar to that of the parent drug; however, the contribution of these metabolites to the overall observed clinical activity of regorafenib cannot be investigated in clinical trials. Therefore, we assessed the pharmacokinetics and pharmacodynamics of regorafenib, M‐2, and M‐5 in vitro and in murine xenograft models. M‐2 and M‐5 showed similar kinase inhibition profiles and comparable potency to regorafenib in a competitive binding assay. Inhibition of key target kinases by all three compounds was confirmed in cell‐based assays. In murine xenograft models, oral regorafenib, M‐2, and M‐5 significantly inhibited tumor growth versus controls. Total peak plasma drug concentrations and exposure to M‐2 and M‐5 in mice after repeated oral dosing with regorafenib 10 mg/kg/day were comparable to those in humans. In vitro studies showed high binding of regorafenib, M‐2, and M‐5 to plasma proteins, with unbound fractions of ~0.6%, ~0.9%, and ~0.4%, respectively, in murine plasma and ~0.5%, ~0.2%, and ~0.05%, respectively, in human plasma. Estimated free plasma concentrations of regorafenib and M‐2, but not M‐5, exceeded the IC50 at human and murine VEGFR2, suggesting that regorafenib and M‐2 are the primary contributors to the pharmacologic activity of regorafenib in vivo.

Bioequivalence study of an oral contraceptive containing ethinylestradiol/drospirenone/levomefolate calcium relative to ethinylestradiol/drospirenone and to levomefolate calcium alone.

BACKGROUND A new tablet formulation containing 0.02 mg ethinylestradiol/3 mg drospirenone/0.451 mg levomefolate calcium (calcium salt containing 0.416 mg L-5-methyltetrahydrofolate) was assessed for bioequivalence compared to the approved oral contraceptive (OC) tablet containing identical amounts of ethinylestradiol and drospirenone and to a tablet containing 0.451 mg levomefolate calcium. STUDY DESIGN Forty-four subjects received in an intraindividual crossover design single doses of the new tablet formulation or the established ethinylestradiol/drospirenone tablet or the levomefolate calcium tablet. RESULTS Bioequivalence was demonstrated for ethinylestradiol, drospirenone and L-5-methyltetrahydrofolate (active moiety of levomefolate calcium) between the investigated tablet formulations. The geometric mean ratios of the AUC((0-tlast)) and C(max) values for all three compounds and their 90% confidence intervals were well within the 80%-125% range generally accepted to demonstrate bioequivalence. CONCLUSION The rate and extent of absorption of ethinylestradiol and drospirenone were not affected by the concomitant administration of levomefolate calcium and vice versa.

Bioequivalence Evaluation of a Folate-Supplemented Oral Contraceptive Containing Ethinylestradiol/Drospirenone/Levomefolate Calcium versus Ethinylestradiol/Drospirenone and Levomefolate Calcium Alone

BACKGROUND Neural tube defects (NTDs) are congenital malformations that occur during early embryonic development. Suboptimal maternal folate status is a well-known risk factor for the occurrence of NTDs, and periconceptional folic acid supplementation has been shown to reduce the risk of NTDs. Folate-supplemented oral contraceptives (OCs) offer a means of improving folate status in women of childbearing potential by increasing their likelihood of having raised folate levels at the time of conception. OBJECTIVE This study aimed to demonstrate bioequivalence of ethinylestradiol (EE), drospirenone and L-5-methyl-tetrahydrofolate (L-5-methyl-THF; active moiety of levomefolate calcium) when taken as a new folate-supplemented OC containing EE/drospirenone/levomefolate calcium, with the respective OC containing EE/drospirenone and a tablet containing levomefolate calcium only. METHODS This was a randomized, open-label, three-period crossover study carried out at a single centre in Germany. The study included 45 healthy women (age range 18-38 years). The women were randomly assigned to single doses of (i) EE 0.03 mg/drospirenone 3 mg/levomefolate calcium 0.451 mg (SAFYRAL®), (ii) EE 0.03 mg/drospirenone 3 mg (Yasmin®), and (iii) levomefolate calcium 0.451 mg, administered using a crossover design, with one or more menstrual cycle washout between doses. The primary variables were maximum concentrations (C(max)) and area under the concentration versus time curve (AUC) values for EE, drospirenone and L-5-methyl-THF. RESULTS The bioavailability of EE and drospirenone was similar after administration of EE/drospirenone/levomefolate calcium and EE/drospirenone. The geometric mean ratios (GMRs) and its 90% confidence intervals (CIs) for AUC values and C(max) were within the pre-specified range (80.00-125.00%) for bioequivalence for EE and drospirenone in both formulations. The bioavailability of L-5-methyl-THF was similar after administration of EE/drospirenone/levomefolate calcium and levomefolate calcium. The respective GMRs and 90% CIs of baseline-uncorrected and -corrected AUC(last) (AUC from time zero to time of last measurable concentration) and C(max) were also within the 80.00-125.00% range. CONCLUSION The novel folate-supplemented OC EE/drospirenone/levomefolate calcium is bioequivalent to the established OC Yasmin® (EE/drospirenone components) and to levomefolate calcium (folate component).