Effect of Multiple‐Dose Dexloxiglumide on the Pharmacokinetics of Oral Contraceptives in Healthy Women

Abstract

This study was undertaken to evaluate the effect of dexloxiglumide, a selective cholecystokinin receptor antagonist, on the pharmacokinetics of a combination oral contraceptive (OC). A single-blind, placebo-controlled, 2-period crossover study was conducted in 24 healthy young female subjects who received Ortho Tri-Cyclen containing ethinyl estradiol (EE, 0.035 mg) and norgestimate (NE, 0.180 mg/0.215 mg/0.250 mg per 7-day phase, respectively) for 5 days (days 17-21) concurrently with either 200 mg dexloxiglumide (3 times a day on days 17-20, followed by a single dose on day 21) or matching placebo during 2 consecutive 28-day OC dosing cycles. Plasma was sampled up to 24 hours for the determination of EE, NE, and 17-deactyl norgestimate (17-DNE, a rapidly formed pharmacologically active metabolite of NE). The geometric mean ratios (GMRs, dexloxiglumide/placebo) of the plasma concentration-time curve over 24 hours with corresponding 90% confidence intervals (CIs) for EE and 17-DNE were 1.21 (1.17-1.26) and 0.92 (0.89-0.95), respectively. The GMRs (90% CI) of C(max) for EE and 17-DNE were 1.15 (1.09-1.20) and 0.93 (0.90-0.96), respectively. Coadministration of OC and dexloxiglumide was well tolerated and safe. Comparable systemic exposure of EE and 17-DNE in the presence and absence of dexloxiglumide suggests that dexloxiglumide treatment is unlikely to interfere with the safety and efficacy of oral contraceptives based on the analysis of the resulting pharmacokinetic profile.

Metabolite Identification, Reaction Phenotyping, and Retrospective Drug-Drug Interaction Predictions of 17-Deacetylnorgestimate, the Active Component of the Oral Contraceptive Norgestimate

“…The reaction phenotyping results clearly indicate a dominant role for CYP3A4-mediated metabolism of NGMN (f m of 0.57) with a lesser role for CYP2B6, even lesser role for CYP2C9, and no role for CYP3A5. The implication of CYP3A4 in the metabolism of NGMN is consistent with numerous clinical trials, wherein it was found that daclatasvir, alitretinoin, rosuvastatin, rifaximin, laropiprant, sofosbuvir, ledipasvir, dolutegravir, dexloxiglumide, tenofovir disoproxil fumarate (a prodrug of tenofovir), saxaglipitin, and raltegravir did not influence the exposures of NGMN (Simonson et al, 2004;Roy et al, 2005;Fig. 4.…”

Dolutegravir Has No Effect on the Pharmacokinetics of Oral Contraceptives With Norgestimate and Ethinyl Estradiol

“…Previous data suggest that oral contraceptive concentrations will not demonstrate wide variability within a cycle. 15-17 Therefore, we also evaluated whether there was a period effect—that is, whether DTG administration in the first part of the cycle had a different effect on NGMN and EE compared with administration in the latter part of the cycle. The results of this analysis demonstrated that the order in which DTG or placebo treatment was given had no effect on concentrations of NGMN and EE.…”

Practical Perspectives on the Use of Tipranavir in Combination With Other Medications: Lessons Learned From Pharmacokinetic Studies

“…Ethinyl estradiol is metabolized by CYP3A, and drugs that affect CYP3A metabolism can lead to loss of ethinyl estradiol effectiveness. 40 Tipranavir/ritonavir decreases the AUC and C max of ethinyl estradiol by 50%, but does not significantly alter the pharmacokinetics of norethindrone. 20 Therefore, when estrogen-based oral contraceptives are coadministered with tipranavir/ritonavir, alternative or additional contraceptive measures are required, and patients should be monitored for signs of estrogen deficiency.…”

“…Ethinyl estradiol is metabolized by CYP3A, and drugs that affect CYP3A metabolism can lead to loss of ethinyl estradiol effectiveness 40 . Tipranavir/ritonavir decreases the AUC and C max of ethinyl estradiol by 50%, but does not significantly alter the pharmacokinetics of norethindrone 20 .…”