Comparison of a transdermal contraceptive patch with a newly sourced adhesive component versus EVRA patch: A double-blind, randomized, bioequivalence and adhesion study in healthy women.

OBJECTIVE: To evaluate the bioequivalence of norelgestromin and ethinyl estradiol (NGMN-EE) and adhesion of a transdermal contraceptive patch containing a newly sourced adhesive component (test) compared with the marketed (reference) patch. STUDY DESIGN: In this randomized, double-blind, 2-way crossover study, healthy women received single 7-day application of both test and reference patches. Treatment phase included two treatment periods of 11 days each separated by a 21-day washout period starting from day of patch removal (day 8) of treatment period 1. Assessments included NGMN and EE pharmacokinetics (PK), adhesion using European Medicines Agency (EMA) 5-point scale, irritation potential and application-site reactions, and safety. Patches were bioequivalent if 90% CIs of ratios of means of test/reference for AUC168h, AUCinf, and Css fell within 80-125%. Patch adhesion was comparable if ratios of mean cumulative adhesion percentage values of test/reference were ≥90.0%. RESULTS: Seventy women were randomized; 57 completed both treatments with ≥80% adhesion (score 0-1). Bioequivalence of test and reference patches was demonstrated as 90% CI of ratio of geometric means for AUC168h, AUCinf, and Css for NGMN and EE fell within 80-125%. Both patches had similar adhesion properties (geometric mean ratio was 100.3% [90% CI, 93.2-107.9]). Similar rates of mild-to-moderate itching (11% vs 10%) and erythema events (79% vs 74%) were reported for test and reference patches, respectively, on day 8. CONCLUSIONS: The test patch with the newly sourced adhesive component is bioequivalent to the currently marketed NGMN-EE transdermal patch and has similar adhesion and irritation potential. IMPLICATIONS STATEMENT: The norelgestromin and ethinyl estradiol transdermal patch containing a newly sourced adhesive component is bioequivalent to the currently marketed patch for both active moieties. Both patches had similar adhesion, irritation potential, and safety profiles.

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.

The pharmacokinetics of 12-week continuous contraceptive patch use.

OBJECTIVES: We sought to assess the change in serum ethinyl estradiol (EE2) and norelgestromin (NGMN) levels over 12 weeks of continuous contraceptive patch use. STUDY DESIGN: We asked participants (n=30) to apply consecutive patches to be worn continuously (without a patch-free interval) for 12 weeks. We collected blood samples at the end of each patch week and two times during weeks 4, 8, and 12 (with the additional blood draw occurring mid-week). Liquid chromatography-tandem triple quadrupole mass spectrometry (LC-MS/MS) was utilized to assess EE2 and NGMN levels. RESULTS: Twenty-seven women completed the study; 26 were compliant with patch use. Ethinyl estradiol levels ranged from 0 to 193 pg/mL over the period. We observed an accumulation over the 12-week time at an estimated rate of 2.15 pg/mL per week (95% confidence interval 0.95-3.35, p<.001). The change in NGMN levels ranged from 0 to 2.52 ng/mL over the 12 weeks (95% confidence interval 0.021-0.019, p=.915). The most common side effects reported were vaginal spotting, breast tenderness and abdominal pain/cramping. There were no serious adverse events reported. CONCLUSION: While the range of weekly EE2 values was quite wide, the absolute values remain low and generally within the expected range described in product labeling. Providers may consider prescribing continuous use of the patch, but given the slow accumulation of EE2 over time, 12 weeks should not be exceeded in the absence of safety data.

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

Ortho Tri-Cyclen, a two-drug cocktail comprised of ethinylestradiol and norgestimate (13-ethyl-17-acetoxy-18, 19-dinor-17α-pregn-4-en-20yn-3 oxime), is commonly prescribed to avert unwanted pregnancies in women of reproductive age. In vivo, norgestimate undergoes extensive and rapid deacetylation to produce 17-deacetylnorgestimate (NGMN), an active circulating metabolite that likely contributes significantly to norgestimate efficacy. Despite being of primary significance, the metabolism and reaction phenotyping of NGMN have not been previously reported. Hence, detailed biotransformation and reaction phenotyping studies of NGMN with recombinant cytochrome P450 (P450), recombinant uridine 5'-diphospho-glucuronosyltransferases, and human liver microsomes in the presence and absence of selective P450 inhibitors were conducted. It was found that CYP3A4 plays a key role in NGMN metabolism with a fraction metabolized (fm) of 0.57. CYP2B6 and to an even lesser extent CYP2C9 were also observed to catalyze NGMN metabolism. Using this CYP3A4 fm value, the predicted plasma concentration versus time area under the curve (AUC) change in NGMN using a basic/mechanistic static model was found to be within 1.3-fold of the reported NGMN AUC changes for four modulators of CYP3A4. In addition to NGMN, we have also elucidated the biotransformation of norgestrel (NG), a downstream norgestimate and NGMN metabolite, and found that CYP3A4 and UGT1A1 have a major contribution to the elimination of NG with a combined fm value of 1. The data presented in this paper will lead to better understanding and management of NGMN-based drug-drug interactions when norgestimate is coadministered with CYP3A4 modulators.

Levonorgestrel butanoate intramuscular injection does not reliably suppress ovulation for 90 days in obese and normal-BMI women: a pilot study.

BACKGROUND: We performed a pilot evaluation of a new formulation of levonorgestrel butanoate (LB) designed to be a long-acting injectable (6 months) contraceptive to determine pharmacodynamic end points in normal-body mass index (BMI) and obese women. STUDY DESIGN: Obese (BMI ≥30 kg/m2) and normal-BMI, otherwise healthy, women received a single intramuscular injection of LB after ovulation was confirmed in a baseline cycle. The primary outcome was return of ovulation in days. RESULTS: A total of 14 women enrolled and completed the study [normal BMI n=9, median BMI 22.7kg/m2 (range 19.4-25.8); obese n=5, median BMI 35.7kg/m2 (30.1-39.2)]. The first 6 subjects (normal BMI=4/9, obese BMI=2/5) received 40 mg of LB, and the remaining 8 received 20 mg. All women except one returned to ovulation prior to 6 months. Return to ovulation occurred earlier in the obese group; 3/5 obese and 0/9 normal BMI subjects returned to ovulation within 90 days (p=.03). No serious adverse events were reported during the study. CONCLUSION: Return to ovulation was earlier than 6 months in both BMI groups but more so in the obese BMI group. IMPLICATIONS: Since return of ovulation was earlier than expected for this LB injectable formulation, additional steps are needed to develop a preparation suitable as a longer-lasting product.

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

BACKGROUND: Dolutegravir (DTG; Tivicay; ViiV Healthcare, Research Triangle Park, NC) is an HIV-1-unboosted integrase inhibitor with no cytochrome P450 or uridine 5'diphosphate-glucuronosyltransferase inhibition or induction. As DTG is administered to HIV-1-infected women receiving oral contraceptives, assessing the potential for drug interactions was warranted. OBJECTIVE: To determine the impact of DTG on the pharmacokinetics (PK) and pharmacodynamics (PD) of a common oral contraceptive, norgestimate/ethinyl estradiol (NGM/EE; Ortho-Cyclen; Ortho-McNeil-Janssen Pharmaceuticals, Inc, Raritan, NJ). METHODS: This randomized, 2-period, double-blind, placebo-controlled study was conducted within 1 menstrual cycle at 1 clinical center in the United States; 16 women were enrolled. Participants received NGM 0.25 mg/EE 0.035 mg throughout the study. During days 1 to 10, they were randomized to receive twice-daily DTG 50 mg or matching placebo with food and switched to the other treatment during days 12 to 21. RESULTS: Ratios of area under the concentration-time curve from time 0 until end of the dosage interval (AUC0-τ), maximum plasma concentration, and concentration at the end of the dosage interval of norelgestromin with DTG treatment to the same PK parameters with placebo treatment were 0.975, 0.890, and 0.932, respectively; for EE, ratios were 1.03, 0.99, and 1.02, respectively. No significant differences in luteinizing hormone, follicle-stimulating hormone, and progesterone were detected on days 1, 10, 11, 21, and 22. DTG steady-state AUC0-τ was similar to historical data. No severe or grade 3/4 adverse events occurred. CONCLUSIONS: DTG had no effect on NGM/EE PK or PD. NGM/EE can be administered with DTG without dose adjustment.

A time-course transcriptional kinetics of the hypothalamic-pituitary-gonadal and hypothalamic-pituitary-adrenal axes in zebrafish eleutheroembryos after exposure to norgestrel.

The objective of the present study was to investigate the effects of norgestrel on the hypothalamic-pituitary-gonadal (HPG) and hypothalamic-pituitary-adrenal (HPA) axes in zebrafish eleutheroembryos. Zebrafish embryos were exposed to different concentrations of norgestrel (0 ng L(-1) , 5 ng L(-1) , 50 ng L(-1) , and 100 ng L(-1) ) for 144 h post fertilization (hpf), and the transcriptional profiles of the HPG and HPA axes were examined every day. Norgestrel modulated the expression of Pgr and Vtg1 messenger (m)RNAs mainly at 96 hpf for all treatment groups. In addition, norgestrel strongly altered the expression of Cyp11a1 mRNA above 5 ng L(-1) (significant upregulation from 48 hpf to 120 hpf and significant downregulation for 144 hpf). Norgestrel treatment could significantly induce expression of Cyp19a1a, Cyp11b, Gnrh2, Gnrh3, and Lhb mRNAs but inhibit transcripts of Hsd11b2 and Crh genes above 5 ng L(-1) at different time points. The transcriptional expression levels of Esr1, Ar, Star, Hsd17b3, Fshb, and Pomc were also mediated by 5 ng L(-1) norgestrel or higher during different exposure periods. Taken together, the overall results imply that the transcriptional changes in zebrafish eleutheroembryos may pose a potential effect on embryonic development, in particular in the brain and gonadogenesis.

[The potential effects of linalool on enantioselective skin permeation of norgestrel].

The purpose of this study is to investigate the enantioselectivity of norgestrel (NG) transdermal permeation and the potential influence of linalool and lipids on the enantioselectivity. In vitro skin permeation studies of NG across the excised rat skins were performed with Valia-Chien diffusion cells, and the permeation samples were analyzed by enantioselective HPLC. The possible enantioselective permeation of NG across intact rat back skin and lipids extracted rat back skin and the influence of linalool were evaluated. The skin permeation rate of dl-NG was two times higher than that of l-NG when donor solutions (EtOH/H2O 2 : 8, v/v) containing l-NG or dl-NG. It may be mainly attributed to the solubility discrepancy between enantiomer and racemate. The enantioselective permeation of dl-NG across intact rat skin was observed when the donor solutions containing dl-linalool. The permeation flux of l-NG was 22% higher than that of d-NG. But interestingly, the enantioselective permeation of dl-NG disappeared under the same experimental condition except that the lipid extracted rat skin was used. Attenuated total reflection-fourier transform infrared spectroscopy analysis of stratum corneum showed that the wave number for asymmetric CH2 stretching vibrations of lipids treated with dl-linalool was greater than that of the control. The results indicated that the enantioselective permeation of NG may be contributed by the interaction between dl-linalool and lipids. More than half of lipids were composed of ceramides. The stereospecific interaction maybe existed among chiral enhancer (linalool), lipids (ceramides) and/or chiral drugs (NG).

Lack of a clinically important pharmacokinetic interaction between sofosbuvir or ledipasvir and hormonal oral contraceptives norgestimate/ethinyl estradiol in HCV-uninfected female subjects.

This study evaluated the potential for a drug-drug interaction between HCV direct-acting antivirals sofosbuvir or ledipasvir and oral hormonal contraceptive (OC) norgestimate/ethinyl estradiol (norgestimate 0.18/0.215/0.25 mg with ethinyl estradiol 25 µg). This was a 112-day, open-label, fixed-sequence pharmacokinetic (PK) study in healthy female subjects that included a lead-in cycle (OC only; N = 21), cycle 1 (OC only; N = 15), cycle 2 (OC + sofosbuvir; N = 15), and cycle 3 (OC + ledipasvir; N = 15). Administration of sofosbuvir with OC did not alter PK of norelgestromin (primary norgestimate metabolite) or ethinyl estradiol. Small increases in norgestrel (secondary norgestimate metabolite) AUC(tau) (19%) and C(tau) (23%) with sofosbuvir were noted. Ledipasvir did not impact PK of norelgestromin or norgestrel but modestly increased ethinyl estradiol C(max) (40%). Sofosbuvir, GS- 331007 (predominant circulating metabolite of SOF), and ledipasvir PK were similar to historical data. Pharmacodynamic markers luteinizing hormone, follicle-stimulating hormone, and progesterone values were generally comparable in all cycles. No loss in contraceptive efficacy is expected upon administration of sofosbuvir or ledipasvir/sofosbuvir with oral contraceptives containing norgestimate and ethinyl estradiol. The use of sofosbuvir or ledipasvir/sofosbuvir FDC with oral contraceptives is permitted.

A simple, rapid and sensitive UFLC-MS/MS method for the quantification of oral contraceptive norgestrel in human plasma and its pharmacokinetic applications.

A simple, rapid and sensitive ultra flow liquid chromatography-tandem mass spectrometry (UFLC-MS/MS) assay for the determination of norgestrel in human plasma was developed using levonorgestrel D6 as an internal standard (IS). Norgestrel and IS were extracted from human plasma via liquid-liquid extraction. Chromatographic separation was achieved on a Zorbax XDB-Phenyl column under isocratic conditions. Detection was done by tandem mass spectrometry, operating in positive ion mode. The protonated precursor to product ion transitions monitored for norgestrel and IS were at m/z 313.30→245.40 and 319.00→251.30 respectively. The method was fully validated as per current regulatory guidelines. Anticoagulant counter ion effect was also assessed with K2EDTA and K3EDTA. The method was validated with a linearity range of 304.356-50 807.337 pg/mL having run time of 2.0 min per sample. The method has shown tremendous reproducibility with intra- and inter-day precision (%CV) less than 11.0% and intra- and inter-day accuracy less than 9.0% of nominal values. The validated method was applied to a pharmacokinetic study in human plasma samples generated after administrating a single oral dose of 0.3 mg norgestrel tablets to healthy female volunteers and has proved to be highly reliable for the analysis of clinical samples.

Effect of the coadministration of daclatasvir on the pharmacokinetics of a combined oral contraceptive containing ethinyl estradiol and norgestimate.

BACKGROUND: Daclatasvir is a highly selective NS5A replication complex inhibitor currently in development for the treatment of chronic hepatitis C infection. Daclatasvir is active at picomolar concentrations and demonstrates in vitro activity against a broad range of HCV genotypes. The primary objective of this study was to assess the effect of daclatasvir on the pharmacokinetics of a combined oral contraceptive containing ethinyl estradiol and norgestimate (Ortho Tri-Cyclen(®)). METHODS: In this open-label single-sequence study, 20 healthy female subjects received ethinyl estradiol and norgestimate for three cycles, with coadministration of daclatasvir in cycle 3. Pharmacokinetics of ethinyl estradiol and the active metabolites of norgestimate (norelgestromin and norgestrel) were assessed in cycles 2 and 3. RESULTS: Adjusted ratios of geometric means and 90% CIs were estimated for the maximum observed plasma concentration (ethinyl estradiol 1.11 [1.02, 1.20], norelgestromin 1.06 [0.99, 1.14] and norgestrel 1.07 [0.99, 1.16]) and area under the plasma concentration-time curve in one dosing interval (ethinyl estradiol 1.01 [0.95, 1.07], norelgestromin 1.12 [1.06, 1.17] and norgestrel 1.12 [1.02, 1.23]). CONCLUSIONS: Coadministration of daclatasvir resulted in no clinically relevant effects on exposure to ethinyl estradiol, norelgestromin or norgestrel.

Effect of saxagliptin on the pharmacokinetics of the active components of Ortho-Cyclen(®), a combined oral contraceptive containing ethinyl estradiol and norgestimate, in healthy women.

Saxagliptin (Onglyza™) is a dipeptidyl peptidase-4 (DPP4) inhibitor for treating type 2 diabetes mellitus. This open-label, randomized, two-way crossover study in 20 healthy female subjects investigated the effect of saxagliptin on the pharmacokinetics (PK) of the active components of a combined oral contraceptive (COC). Subjects received either COC (Ortho-Cyclen(®)) once daily (QD) for 21 days, then 5 mg saxagliptin QD + COC QD for 21 days, or vice versa. Coadministration of saxagliptin and COC did not alter the steady-state PK of the primary active oestrogen (ethinyl estradiol) or progestin (norelgestromin) COC components. The area under the concentration-time curve (AUC) and peak plasma concentration (Cmax) of an active metabolite of norelgestromin (norgestrel) were increased by 13 and 17%, respectively, a magnitude that was not considered clinically meaningful. Coadministration of saxagliptin and COC in this study was generally well-tolerated. Saxagliptin can be co-prescribed with an oestrogen/progestin combination for women taking oral contraceptive.

Effect of raltegravir on estradiol and norgestimate plasma pharmacokinetics following oral contraceptive administration in healthy women.

AIMS: Oral contraceptives such as norgestimate-ethinyl estradiol (Ortho Tri-Cyclen®) are commonly prescribed in the HIV-infected patient population. A placebo-controlled, randomized, two-period crossover study in healthy HIV-seronegative subjects was conducted to assess the effect of raltegravir on the pharmacokinetics of the estrogen and progestin components of norgestimate-ethinyl estradiol [ethinyl estradiol (EE) and norelgestromin (NGMN), an active metabolite of norgestimate (NGT)]. METHODS: In each of two periods, nineteen healthy women established on norgestimate-ethinyl estradiol contraception (21 days of active contraception; 7 days of placebo) received either 400 mg raltegravir or matching placebo twice daily on days 1-21. Pharmacokinetics were analysed on day 21 of each period. RESULTS: The geometric mean ratio (GMR) and 90% confidence interval (CI) for the EE component of norgestimate-ethinyl estradiol when co-administrated with raltegravir relative to EE alone was 0.98 (0.93-1.04) for the area under the concentration-time curve from 0 to 24 h (AUC(0-24 h) ) and 1.06 (0.98-1.14) for the maximum concentration of drug in the plasma (C(max) ); the GMR (90% CI) for the NGMN component of norgestimate-ethinyl estradiol when co-administered with raltegravir relative to NGMN alone was 1.14 (1.08-1.21) for AUC(0-24 h) and 1.29 (1.23-1.37) for C(max) . There were no discontinuations due to a study drug-related adverse experience, nor any serious clinical or laboratory adverse experience. CONCLUSIONS: Raltegravir has no clinically important effect on EE or NGMN pharmacokinetics. Co-administration of raltegravir and an oral contraceptive containing EE and NGT was generally well tolerated; no dose adjustment is required for oral contraceptives containing EE and NGT when co-administered with raltegravir.

The effect of efavirenz on the pharmacokinetics of an oral contraceptive containing ethinyl estradiol and norgestimate in healthy HIV-negative women.

BACKGROUND: Women of childbearing age represent a growing proportion of people living with HIV. Preventing pregnancy is important in HIV-infected women receiving efavirenz as part of their antiretroviral therapy. METHODS: The effects of coadministration of efavirenz (600 mg once daily) on the pharmacokinetics (PK) of the active components (ethinyl estradiol [EE] and 17-deacetyl norgestimate [NGMN]) of Ortho Cyclen(®) (Ortho-McNeil-Janssen Pharmaceuticals, Inc., Raritan, NJ, USA) were investigated in 28 healthy HIV-negative women. The peak plasma concentration (C(max)), area under the concentration-time curve for a dosing interval (AUC([τ])), and lowest plasma concentration (C(min)) for EE and NGMN during cycles of treatment with Ortho Cyclen with and without coadministration of efavirenz were compared. Additionally, a post hoc exploratory analysis was conducted to assess the effect of efavirenz on the PK of an additional progestin, levonorgestrel (LNG). RESULTS: Exposures to EE were similar during coadministration of efavirenz and Ortho Cyclen to those during administration of Ortho Cyclen alone. Exposures to NGMN were substantially decreased following coadministration of efavirenz and Ortho Cyclen (adjusted geometric means for C(max), AUC([τ]) and C(min) decreased by 46%, 64% and 82%, respectively) compared with Ortho Cyclen alone. Consistent with NGMN, LNG exposures were decreased 80-86% by efavirenz. CONCLUSIONS: Although efavirenz had no significant effect on the PK of EE, exposures to the progestin components of Ortho Cyclen, NGMN and LNG, were substantially reduced. The results reinforce the need to use reliable methods of barrier contraception, even when taking oral contraceptives and efavirenz.

The effect of atazanavir/ritonavir on the pharmacokinetics of an oral contraceptive containing ethinyl estradiol and norgestimate in healthy women.

BACKGROUND: Coadministration of oral contraceptives with protease inhibitors is complicated by drug interactions. An open-label three-period single-sequence study assessed the effect of coadministration of atazanavir (ATV)/ritonavir (RTV) with Ortho Tri-Cyclen(®) and with Ortho Tri-Cyclen(®) LO (Ortho-McNeil-Janssen Pharmaceuticals, Inc., Raritan, NJ, USA) on the pharmacokinetics (PK) of ethinyl estradiol (EE), norgestimate (NGM), ATV and RTV. METHODS: A total of 20 healthy women aged 18-45 years received study treatments. In the lead-in period and in period 1, participants received a full cycle of Ortho Tri-Cyclen (EE 35 µg with NGM 0.18/0.215/0.25 mg) from days 1-28. In period 2, participants received a full cycle of Ortho Tri-Cyclen LO (EE 25 µg with NGM 0.18/0.215/0.25 mg) plus ATV/RTV (300/100 mg once daily) on days 29-42. PK assessments were performed on days 14 and 42 in periods 1 and 2, respectively. RESULTS: ATV/RTV with dose-normalized EE/NGM resulted in geometric mean reductions of 16% in EE peak plasma concentration (C(max)), 19% in EE area under the concentration-time curve for a dosing interval (AUC([τ])) and 37% in EE lowest plasma concentration (C(min)), compared with EE 35 µg with NGM in the absence of ATV/RTV. NGM with EE and ATV/RTV 300/100 mg once daily resulted in increases of approximately 68%, 85% and 102% in 17-deacetyl NGM C(max), AUC((τ)) and C(min), respectively. Two participants discontinued the study because of adverse events. CONCLUSIONS: ATV/RTV with Ortho Tri-Cyclen was well-tolerated and reductions in EE were not predicted to decrease contraceptive efficacy if the formulation contained ≥30 µg of EE.

Contraceptive efficacy of oral and transdermal hormones when co-administered with protease inhibitors in HIV-1-infected women: pharmacokinetic results of ACTG trial A5188.

BACKGROUND: Pharmacokinetic (PK) interactions between lopinavir/ritonavir (LPV/r) and transdermally delivered ethinyl estradiol (EE) and norelgestromin (NGMN) are unknown. METHODS: Using a standard noncompartmental PK analysis, we compared EE area under the time-concentration curve (AUC) and NGMN AUC during transdermal contraceptive patch administration in HIV-1-infected women on stable LPV/r to a control group of women not on highly active antiretroviral therapy (HAART). In addition, EE AUC after a single dose of a combination oral contraceptive pill including EE and norethindrone was measured before patch placement and was compared with patch EE AUC in both groups. Contraceptive effects on LPV/r PKs were estimated by measuring LPV/r AUC at baseline and during week 3 of patch administration. RESULTS: Eight women on LPV/r, and 24 women in the control group were enrolled. Patch EE median AUC0-168 h was 45% lower at 6010.36 pg·h·mL in those on LPV/r versus 10911.42 pg·h·mL in those on no HAART (P = 0.064). Pill EE median AUC0-48 hours was similarly 55% lower at 344.67 pg·h·mL in those on LPV/r versus 765.38 pg·h·mL in those on no HAART (P = 0.003). Patch NGMN AUC0-168 h however, was 138.39 ng·h·mL, 83% higher in the LPV/r group compared with the control AUC of 75.63 ng·h·mL (P = 0.036). After 3 weeks on the patch, LPV AUC0-8 h decreased by 19%, (P = 0.156). CONCLUSIONS: Although PKs of contraceptive EE and NGMN are significantly altered with LPV/r, the contraceptive efficacy of the patch is likely to be maintained. Larger studies are indicated to fully assess contraceptive efficacy versus risks of the transdermal contraceptive patch when co-administered with protease inhibitors.

Effect of laropiprant, a PGD2 receptor 1 antagonist, on estradiol and norgestimate pharmacokinetics after oral contraceptive administration in women.

Laropiprant is a prostaglandin D2 receptor 1 antagonist that is being developed in combination with niacin for the treatment of dyslipidemia. This randomized clinical study evaluated the effect of laropiprant on the pharmacokinetics of ethinyl estradiol (EE) and norelgestromin (NGMN), the principal circulating metabolite of norgestimate, in healthy women receiving 3 or more months of an oral contraceptive (Ortho Tri-Cyclen; Ortho-McNeil Pharmaceutical, Raritan, NJ), which contains EE and norgestimate. Twenty-one female subjects with normal menstrual cycles received the oral contraceptive on Days 1 to 21 during two consecutive contraceptive cycles. Subjects received double-blind 40 mg/day laropiprant or placebo on Days 1 to 21 of each contraceptive cycle. Plasma samples were collected predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose on Day 21 to measure area under the plasma concentration-time curve from 0 to 24 hours (AUC0-24hr) and maximum concentration observed in plasma (Cmax) of EE and NGMN. Comparability would be declared if the 90% confidence intervals for the geometric mean ratio of AUC0-24hr and Cmax in the absence and presence of laropiprant were within predefined bounds (0.80-1.25). The estimated geometric mean ratios (90% confidence intervals) of EE and NGMN, respectively, were 1.08 (1.04-1.13) and 0.97 (0.94-0.99) for AUC0-24hr and 1.16 (1.06-1.27) and 1.00 (0.94-1.06) for Cmax. The 90% confidence intervals for the geometric mean ratio of EE Cmax minimally exceeded the prespecified bounds; the other relevant pharmacokinetic parameters fell within the predefined bounds. Coadministration of 40 mg laropiprant with the oral contraceptive did not lead to clinically meaningful alterations in the pharmacokinetics of EE or NGMN.

Lack of effect of tenofovir disoproxil fumarate on pharmacokinetics of hormonal contraceptives.

STUDY OBJECTIVE: To assess the potential for a drug-drug interaction between a representative hormonal contraceptive (norgestimate-ethinyl estradiol) and tenofovir disoproxil fumarate (tenofovir DF), a prodrug of tenofovir, when coadministered. DESIGN: Thirty-day, open-label, fixed-sequence, pharmacokinetic drug-drug interaction study. SETTING: Single clinical phase I center. PARTICIPANTS: Twenty nonpregnant and nonlactating women aged 19-45 years who were taking a norgestimate-ethinyl estradiol oral contraceptive. INTERVENTION: Each woman received norgestimate-ethinyl estradiol alone on study days 1-22, followed by norgestimate-ethinyl estradiol plus tenofovir DF 300 mg once/day for 7 days during two consecutive 28-day contraceptive cycles. MEASUREMENTS AND MAIN RESULTS: Pharmacokinetic assessments were performed over 24 hours on study days 1 and 29 (corresponding to matching days [day 21] of the two contraceptive cycles). Serum or plasma concentrations of tenofovir, norgestimate and its active metabolite deacetyl norgestimate, and ethinyl estradiol were measured by high-performance liquid chromatography-tandem mass spectrometry assays. Geometric mean ratios (90% confidence intervals) for the pharmacokinetic parameters for deacetyl norgestimate and ethinyl estradiol were estimated by using analysis of variance and compared with the no-effect criterion for bioequivalence. The tenofovir pharmacokinetic parameters were compared with historical controls. Pharmacokinetic parameters for deacetyl norgestimate and ethinyl estradiol were unaltered by coadministration of tenofovir DF. The tenofovir pharmacokinetic parameters in subjects receiving norgestimate-ethinyl estradiol were consistent with historical control data for tenofovir. CONCLUSION: Tenofovir DF and norgestimate-ethinyl estradiol are not involved in a clinically significant drug-drug interaction; tenofovir DF did not affect the steady-state pharmacokinetics of norgestimate or ethinyl estradiol, including the concentration at the end of the dosing interval. Both drugs were well tolerated when coadministered. Tenofovir DF is unlikely to affect the pharmacokinetics of hormonal oral contraceptives.

Determination of norelgestromin in rabbit plasma by LC-MS/MS and its application to the pharmacokinetic study of ORTHO EVRA.

A simple, sensitive and rapid method is presented for the determination of norelgestromin using LC-MS/MS, interfaced via an electrospray ionization (ESI) probe, operating in the positive ion mode with multiple reaction monitoring (MRM). The method was developed and validated over the concentration range of 0.05-20 ng/ml, and showed excellent linearity. The intra- and inter-assay accuracy error and precision were ranging from -2.3% to 6.0% of nominal values and 2.2% to 7.8% over the three concentration levels evaluated. The concentration of formic acid in mobile phase was optimized to achieve satisfactory injection reproducibility and sensitivity, and sample preparation was optimized, with only 1.6 ml organic solvents used in performing the liquid-liquid extraction. The method has been successfully applied to a pharmacokinetic study of the ORTHO EVRA patch in rabbits.