First-in-human study of the PARP/tankyrase inhibitor E7449 in patients with advanced solid tumours and evaluation of a novel drug-response predictor.

BACKGROUND: This phase 1 study examined the safety, maximum-tolerated dose (MTD) and antitumour activity of E7449, a novel PARP 1/2 and tankyrase 1/2 inhibitor. METHODS: E7449 was orally administered once daily in 28-day cycles to patients with advanced solid tumours (50-800-mg doses). Archival tumour samples from consenting patients were evaluated for the expression of 414 genes in a biomarker panel (2X-121 drug-response predictor [DRP]) found to be predictive of the response to E7449 in cell lines. RESULTS: Forty-one patients were enrolled (13 pancreatic, 5 ovarian, 4 each with breast, lung or colorectal cancer and 11 with other tumour types). The most common grade ≥3 treatment-related adverse event was fatigue (n = 7, 17.1%). Five patients experienced a dose-limiting toxicity (fatigue, n = 4, 800 mg; anaphylaxis, n = 1, 600 mg) for an MTD of 600 mg. E7449 exhibited antitumour activity in solid tumours, including 2 partial responses (PRs), and stable disease (SD) in 13 patients, which was durable (>23 weeks) for 8 patients. In 13 patients, the 2X-121 DRP identified those achieving PR and durable SD. E7449 showed good tolerability, promising antitumour activity and significant concentration-dependent PARP inhibition following 50-800-mg oral dosing. CONCLUSION: The results support further clinical investigation of E7449 and its associated biomarker 2X-121 DRP. CLINICAL TRIAL REGISTRATION: www.ClinicalTrials.gov code: NCT01618136.

Safety and tolerability of a new low-dose contraceptive patch in obese and nonobese women.

OBJECTIVE: The safety and tolerability of a new low-dose levonorgestrel/ethinyl estradiol (LNG/EE) contraceptive patch was compared with 2 combination oral contraceptives in 2 clinical studies in which approximately 30% of enrolled participants were obese. STUDY DESIGN: Two phase 3, open-label, randomized, parallel-group, multicenter trials compared the LNG/EE contraceptive patch (n = 1579) with combination oral contraceptives (n = 581) in healthy women 17-40 years of age. Combination oral contraceptives were LNG 100 µg per EE 20 µg (combination oral contraceptive 20; n = 375) or LNG 150 µg per EE 30 µg (combination oral contraceptive 30; n = 206). Safety and tolerability data from the 2 trials were evaluated in integrated safety analyses. RESULTS: Treatment-emergent adverse events of 2% or greater in the LNG/EE contraceptive patch were nasopharyngitis (5.2%), nausea (4.1%), upper respiratory infection (3.5%), headache (3.4%), sinusitis (2.9%), cervical dysplasia (2.3%), and urinary tract infection (2.1%). Including skin reaction-related treatment-emergent adverse events, the proportion of women who experienced any treatment-emergent adverse event was similar among women randomized to the contraceptive patch (47.5%), the combination oral contraceptive 20 (47.4%), or the combination oral contraceptive 30 (46.8%). The incidence of treatment-emergent adverse events was similar in obese vs nonobese participants in all groups. Serious adverse events occurred in less than 1% of participants in any of the treatment groups. CONCLUSION: The LNG/EE contraceptive patch and combination oral contraceptives were well tolerated and associated with similar treatment-emergent adverse event incidences in obese and nonobese women.

A novel drug specific mRNA biomarker predictor for selection of patients responding to dovitinib treatment of advanced renal cell carcinoma and other solid tumors.

PURPOSE: Dovitinib is a receptor tyrosine kinase inhibitor of VEGFR1-3, PDGFR, FGFR1/3, c-KIT, FLT3 and topoisomerase 1 and 2. The drug response predictor (DRP) biomarker algorithm or DRP-Dovitinib is being developed as a companion diagnostic to dovitinib and was applied retrospectively. PATIENTS AND METHODS: Archival tumor samples were obtained from consenting patients in a phase 3 trial comparing dovitinib to sorafenib in renal cell carcinoma patients and the DRP-Dovitinib was applied. The biomarker algorithm combines the expression of 58 messenger RNAs relevant to the in vitro sensitivity or resistance to dovitinib, including genes associated with FGFR, PDGF, VEGF, PI3K/Akt/mTOR and topoisomerase pathways as well as ABC drug transport, and provides a likelihood score between 0-100%. RESULTS: The DRP-Dovitinib divided the dovitinib treated RCC patients into two groups, sensitive (n = 49, DRP score >50%) or resistant (n = 86, DRP score ≤ 50%) to dovitinib. The DRP sensitive population was compared to the unselected sorafenib arm (n = 286). Median progression-free survival (PFS) was 3.8 months in the DRP sensitive dovitinib arm and 3.6 months in the sorafenib arm (hazard ratio 0.71, 95% CI 0.51-1.01). Median overall survival (OS) was 15.0 months in the DRP sensitive dovitinib arm and 11.2 months in the sorafenib arm (hazard ratio 0.69, 95% CI 0.48-0.99). The observed clinical benefit increased with increasing DRP score. At a cutoff of 67% the median OS was 20.6 months and the median PFS was 5.7 months in the dovitinib arm. The results were confirmed in five smaller phase II trials of dovitinib which showed a similar trend. CONCLUSION: The DRP-Dovitinib shows promise as a potential biomarker for identifying advanced RCC patients most likely to experience clinical benefit from dovitinib treatment, subject to confirmation in an independent prospective trial of dovitinib in RCC patients.

Risk of hyperkalemia in women taking ethinylestradiol/drospirenone and other oral contraceptives.

BACKGROUND: The oral contraceptive ethinyl estradiol 0.03 mg/drospirenone 3 mg (EE/DRSP) contains a progestin component that possesses potassium-sparing diuretic activity similar to spironolactone. We sought to determine whether EE/DRSP use might lead to adverse effects possibly attributable to hyperkalemia. STUDY DESIGN: This was a matched cohort study in which we identified oral contraceptive (OC) initiators between July 2001 and June 2004 within a large, US health plan. We matched EE/DRSP initiators to other OC initiators in a 1:2 ratio on the basis of a prediction model (propensity score) of EE/DRSP initiation that incorporated dozens of characteristics. We identified insurance claims mentioning hyperkalemia, related clinical outcomes (electrolyte disturbances, arrhythmia, syncope, myocardial infarction) and verified the underlying condition through medical record review. RESULTS: There were 22,429 EE/DRSP initiators matched to 44,858 other OC initiators, with an average follow-up of 7.6 months. A composite clinical surrogate hyperkalemia end point occurred with equal frequency in the compared groups [118 cases in EE/DRSP and 260 in comparators; rate ratio (RR) 0.9, 95% confidence interval (CI) 0.7-1.1]. The individual hyperkalemia surrogate end points exhibited similar results. One EE/DRSP initiator and four comparators were diagnosed specifically with hyperkalemia (RR 0.5, 95% CI 0.0-4.9). The results were not different when we accounted for changes in OC use during follow-up. CONCLUSION: EE/DRSP initiators are no more likely than other OC initiators to experience hyperkalemia or related clinical outcomes which could be caused by hyperkalemia during follow-up.

Long-term safety of drospirenone-estradiol for hormone therapy: a randomized, double-blind, multicenter trial.

OBJECTIVE: The purpose of this multicenter, double-blind, randomized, parallel-group study was to determine the effect of thirteen 28-day cycles of drospirenone combined with estradiol, compared with estradiol alone, on the endometrium of postmenopausal women. DESIGN: Postmenopausal women not on hormone therapy but with an intact uterus were enrolled (N = 1,147); 1,142 were evaluated. Participants were randomly assigned to treatment with 1.0 mg of estradiol alone (E(2) monotherapy) or 1.0 mg of estradiol plus 0.5, 1.0, 2.0, or 3.0 mg of drospirenone (DRSP/E(2)). Endometrial biopsies were performed at baseline, at 7 months if indicated, and at study end in the 13th month. Safety was evaluated with peripheral blood samples for hematology, liver and renal function, and lipids, along with vital signs and interval medical evaluations. RESULTS: When compared with estradiol alone, combinations of drospirenone and estradiol were effective in protecting against endometrial hyperplasia. The probability of hyperplasia was 0.060 (95% CI, 0.043-0.078) for the E(2) monotherapy group, 0.007 for the 2-mg DRSP/E(2) group, and nonsignificant for the remaining drospirenone/estradiol groups. Endometrial bleeding decreased in all treatment groups over time. The combination of drospirenone and E(2) relieved menopausal symptoms and resulted in improvements in health-related quality-of-life measures. There were no significant adverse events, and effects on triglycerides, total cholesterol, and high-density lipoprotein cholesterol were positive. CONCLUSIONS: The use of drospirenone combined with estradiol provides protection against endometrial hyperplasia, reduces endometrial bleeding with time, and relieves menopausal symptoms. There were no safety issues and blood pressure was reduced in women with hypertension.

Efficacy of a new low-dose oral contraceptive with drospirenone in premenstrual dysphoric disorder.

OBJECTIVE: To compare the efficacy of a new low-dose oral contraceptive pill (OCP) formulation with placebo in reducing symptoms of premenstrual dysphoric disorder. METHODS: This multicenter, double-blind, randomized clinical trial consisted of 2 run-in and 3 treatment cycles with daily symptom charting; 450 women with symptoms of premenstrual dysphoric disorder were randomized to either placebo or an OCP formulation containing drospirenone 3 mg and ethinyl estradiol 20 microg. Hormones were administered for 24 days, followed by 4 days of inactive pills (24/4). RESULTS: Scores on the total Daily Record of Severity of Problems decreased by -37.49 in the drospirenone/ethinyl estradiol group and by -29.99 in the placebo group (adjusted mean difference -7.5, 95% confidence interval [CI] -11.2 to -3.8; P < .001 by rank analysis of covariance). Mood symptom scores were reduced by -19.2 and -15.3 in active-treatment and placebo groups, respectively (adjusted mean difference -3.9, 95% CI -5.84 to -2.01; P = .003); physical symptom scores were reduced by -10.7 and -8.6 in active-treatment and placebo groups, respectively (adjusted mean difference -2.1, 95% CI -3.3 to -0.95; P < .001); and behavioral symptom scores were reduced by -7.7 and -6.2 in active-treatment and placebo groups, respectively (adjusted mean difference -1.5, 95% CI -2.251 to -0.727; P < .001). Response, defined as a 50% decrease in daily symptom scores, occurred in 48% of the active-treatment group and 36% of the placebo group (relative risk 1.7, 95% CI 1.1 to 2.6; P = .015) and corresponds to a number-needed-to-treat of 8 patients. CONCLUSION: A 24/4 regimen of drospirenone 3 mg and ethinyl estradiol 20 mug improves symptoms associated with premenstrual dysphoric disorder. LEVEL OF EVIDENCE: I.

New contraceptive patch wearability assessed by investigators and participants in a randomized phase 3 study.

OBJECTIVE: To evaluate skin irritation and patch adhesiveness of a new weekly low-dose levonorgestrel (LNG) and ethinyl estradiol (EE) contraceptive patch (LNG/EE patch). STUDY DESIGN: This analysis was part of an open-label, parallel-group, multicenter, phase 3 study that randomized healthy women to the LNG/EE patch (one patch weekly for three consecutive weeks, followed by a patch-free week for 13 cycles) or to an oral contraceptive for six cycles followed by seven LNG/EE patch cycles. Participants selected patch application sites of abdomen, buttock or upper torso. Investigators rated patch adhesiveness and skin irritation using standardized scales. Participants rated skin irritation and itching daily using standardized scales and recorded patch fall-off on daily diary cards. RESULTS: A total of 32,508 patches were applied (n=1273). At the five clinic visits in which investigators rated the patches, they rated adhesiveness=0 (no lift) for ≥84% of participants and skin irritation=absent/mild for 97% of patches. Participants reported that 2-3.7% of patches fell off and rated skin irritation as absent or mild for 92- 95% of patches, according to site. CONCLUSION: Investigator- and participant-rated assessments of LNG/EE patch adhesiveness and irritation demonstrated a low incidence of patch detachment, skin irritation and pruritus. IMPLICATIONS STATEMENT: This secondary analysis of a phase 3 clinical trial of a new weekly low-dose LNG and EE contraceptive patch, which used assessment by both investigators and participants, observed a low incidence of skin irritation, pruritus and patch detachment.

Self-reported and verified compliance in a phase 3 clinical trial of a novel low-dose contraceptive patch and pill.

OBJECTIVE: Pregnancy rates in US contraceptive clinical trials are increasing due to decreased treatment compliance. This study compared compliance with a new low-dose levonorgestrel (LNG) and ethinyl estradiol (EE) contraceptive patch (CP, Twirla™) with that of a low-dose combination oral contraceptive (COC) in a demographically diverse population. STUDY DESIGN: This analysis was part of an open-label, parallel-group, multicenter phase 3 study that randomized healthy sexually active women (17-40years) to 13cycles of LNG/EE CP or 6cycles of COC, then 7cycles of LNG/EE CP. We defined self-reported compliance as cycles that, according to diaries, show 21days of patch wear without missed days or any patch worn >7days or 21days of pill-taking without missed pill days. We verified compliance by detectable plasma presence of LNG and EE at cycles 2, 6, and 13. RESULTS: Of the intention-to-treat population with diary information (N=1328, mean age 26.4years, 46% minorities, 33% obese), 10.0% of the CP (n=998) versus 21.2% of the COC group (n=330) self-reported noncompliance after 6cycles (p<.001). Laboratory assessments verified 10-14% of participants in both groups as noncompliant. Self-reported perfect use did not vary between obese [body mass index (BMI) ≥30kg/m(2)] versus nonobese (BMI <30kg/m(2)) participants in both groups or when stratified by age, education, or race/ethnicity in the CP group. CONCLUSIONS: Self-reported compliance was significantly greater in the CP than COC group and did not vary by obesity status. Discrepancies between self-reported and verified compliance question reliability of patient diaries. IMPLICATIONS STATEMENT: This paper, based on an analysis of a phase 3 trial, shows that compliance was significantly greater with a new weekly transdermal CP than with a once-daily COC in obese as well as nonobese participants. Discrepancies between self-reported compliance and laboratory-verified compliance raise questions regarding the reliability of patient diaries.

Short-term angiopeptin therapy and the incidence of graft vessel disease after heart transplantation.

BACKGROUND: Graft vessel disease, the major limitation for long-term success after heart transplantation, is triggered by injury to the graft vessel endothelium, resulting in the expression of adhesion molecules, the migration of leukocytes into the graft, and the release of growth factors. Angiopeptin, a stable analog of somatostatin, is a growth-hormone inhibitor with additional anti-proliferative effects. We evaluated angiopeptin for prevention of graft vasculopathy after cardiac transplantation in the first prospective, randomized, double-blind, clinical trial. METHODS: Thirty-one patients received treatment with either angiopeptin (n = 13) or placebo (n = 18). Patients were randomized according to the presence of hypercholesterolemia, recipient cytomegalovirus-antibody status, and donor age. All patients received standard triple-drug immunosuppression. Angiopeptin 1.5 mg or placebo was given subcutaneously immediately before surgery and twice a day after transplantation from Day 1 to Day 14. Furthermore, 1.5 mg was added to each liter of cardioplegic solution, 1.5 mg was given intravenously during surgery, and another 3 mg was given during the first 6 post-operative hours. During the first post-operative year, angiopeptin 1.5 mg or placebo was added to each treatment for acute rejection (twice a day subcutaneously). Baseline angiography was performed within the first 4 post-operative weeks and annually thereafter. Twenty-three patients each underwent an additional intracoronary ultrasound. RESULTS: One- and 4-year survival rates were comparable: 85% and 85% for the group receiving angiopeptin, and 89% and 78% for the placebo group, respectively. One patient in the control group died of myocardial infarction caused by graft vessel disease. Although the mean number of rejection and infection episodes was similar, the overall incidence of newly occurring graft vessel disease after 2 and 4 years was greater in the control cohort: 9% vs 38% after 2 years and 27% vs 44% after 4 years (p = 0.183, 0.448). Comparison of the results of intracoronary ultrasound performed in a sub-group of patients confirmed that trend: the modified Stanford score, the mean intimal thickness, and the mean intimal index were lower in the angiopeptin group. Again, because of the relatively small number of patients available for evaluation, the difference did not reach statistical significance. CONCLUSIONS: Short-term peri-operative angiopeptin treatment along with additional injections during rejection episodes within the first year resulted in a marked decrease in graft vessel disease 2 and 4 years after heart transplantation. Based on our results, continuous, long-term application of slow-release angiopeptin could significantly decrease or even prevent graft vessel disease.

Low-dose levonorgestrel and ethinyl estradiol patch and pill: a randomized controlled trial.

OBJECTIVE: To compare a new low-dose levonorgestrel and ethinyl estradiol contraceptive patch (Patch) with a combination oral contraceptive (Pill; 100 micrograms levonorgestrel, 20 micrograms ethinyl estradiol) regarding efficacy, safety, compliance, and unscheduled uterine bleeding. METHODS: Women (17-40 years; body mass index 16-60) were randomized in a 3:1 ratio to one of two groups: Patch only (13 cycles) or Pill (six cycles) followed by Patch (seven cycles). Investigators evaluated adverse events during cycles 2, 4, 6, 9, and 13. Participants recorded drug administration and uterine bleeding on daily diary cards. Compliance was assessed by measuring levonorgestrel and ethinyl estradiol plasma levels. Pearl Index (pregnancies per 100 woman-years) was calculated to evaluate efficacy. RESULTS: Participants (N=1,504) were randomized to Patch (n=1,129) or Pill (n=375). Approximately 30% were obese, more than 40% were racial or ethnic minorities, and more than 55% were new users of hormonal contraceptives. Laboratory-verified noncompliance (undetectable plasma drug levels) was 11% of Patch and 12.6% of Pill users at cycle 6. Pearl Indices (95% confidence intervals) for the intention-to-treat population (cycles 1-6) were 4.45 (2.34-6.57) for Patch and 4.02 (0.50-7.53) for Pill; excluding laboratory-verified noncompliant participants, Pearl Indices were 2.82 (0.98-4.67) for Patch and 3.80 (0.08-7.52) for Pill (differences not statistically significant). Incidence of unscheduled bleeding and incidence and severity of adverse events were similar for both contraceptives (no statistically significant difference). CONCLUSIONS: Efficacy and safety of the new contraceptive Patch are comparable to those of a Pill. Laboratory-verified noncompliance and bleeding profile are similar between the two treatments. The Patch was well tolerated. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT01181479. LEVEL OF EVIDENCE: I.

Therapeutically equivalent pharmacokinetic profile across three application sites for AG200-15, a novel low-estrogen dose contraceptive patch.

BACKGROUND: AG200-15 Agile Patch (AP) is a novel 7-day contraceptive patch providing ethinyl estradiol (EE) exposure comparable to low-dose combination oral contraceptives. This study determined whether application of the AP to three different anatomical sites (lower abdomen, buttock and upper torso) influences the pharmacokinetic profile of EE and levonorgestrel (LNG). STUDY DESIGN: In this open-label, three-period, crossover study, 24 subjects were randomized to one of six treatment sequences; each included application of patch to abdomen, buttock and upper torso, with the AP worn on one site for 7 days. After a 7-day washout, a new patch was applied to the next anatomical site. Multiple blood samples were collected up to 240 h after patch application. RESULTS: For plasma EE levels, median time to maximum drug concentration (Tmax, 24-48 h) and mean maximum concentration (Cmax, 47.9-61.5 pg/mL) were similar among application sites. Compared with lower abdomen, EE exposure was higher (16%-30%) at buttock and upper torso (15%-22%). For plasma LNG levels, median Tmax (72-120 h) and mean Cmax (1436-1589 pg/mL) were similar across application sites. Compared with lower abdomen, LNG exposure was higher at buttock (1%-7%) and upper torso (16%-17%). No serious adverse events (AEs) or AE-related discontinuations occurred. The most common treatment-emergent AEs were nausea, application site pruritus and headache, with frequencies comparable across anatomical sites. CONCLUSIONS: Absorption from the abdomen was slightly lower versus other sites; however, exposure to EE and LNG for all sites was therapeutically equivalent. The AP was well tolerated at all three anatomical sites.

Pharmacokinetics and adhesion of the Agile transdermal contraceptive patch (AG200-15) during daily exposure to external conditions of heat, humidity and exercise.

BACKGROUND: This study compares the pharmacokinetic profile, adhesion and safety of the AG200-15 Agile Patch (AP), a novel contraceptive patch releasing low-dose ethinyl estradiol (EE) and levonorgestrel (LNG), during wear under external conditions of heat, humidity and exercise versus normal activities. STUDY DESIGN: This open-label, three-period, five-treatment, crossover study randomized 24 healthy women to one of six external condition sequences. Each sequence included one normal wear and two external conditions periods. Participants wore the AP for 7 days under normal conditions or conditions of daily sauna, treadmill, whirlpool or cool water immersion, with a 7-day washout between treatments. Blood samples were collected for pharmacokinetic evaluations. RESULTS: Twenty-four subjects completed the study. For EE, the mean maximum concentration level (Cmax), area under the plasma concentration-time curve from time 0 to 168 h (AUC(0-168)) and area under the plasma concentration-time curve from time 0 to infinity (AUC(0-inf)) were higher during normal conditions compared with all external conditions (geometric means ratio range: 80%-93%), except cool water. Mean steady-state concentrations (C(ss)) of EE were highest under normal conditions, followed by cool water, sauna, whirlpool and treadmill. The LNG mean C(max), AUC(0-168), AUC(0-inf) and C(ss) were higher under normal wear versus all other conditions (geometric means ratios: 75%-82%), with the exception of AUC(0-168), AUC(0-inf) and C(ss) for cold water. Median times to maximum concentration (Tmax) for EE and LNG were comparable across conditions. Patch adhesion was excellent under all conditions. Adverse events were mild, with none serious or leading to discontinuation. CONCLUSIONS: Although slightly lower mean drug concentration levels were observed for whirlpool, treadmill and sauna, drug concentrations under all conditions were well within therapeutic ranges established for the AP during normal wear and within ranges reported for low-dose combination oral contraceptives. Patch adhesion was excellent; the AP was safe and well tolerated under all conditions.

Ovarian activity in obese and nonobese women treated with three transdermal contraceptive patches delivering three different doses of ethinyl estradiol and levonorgestrel.

BACKGROUND: The effect of obesity on ovarian follicular suppression in women using low-estrogen dose contraceptive patches has not been determined. STUDY DESIGN: A Phase II, parallel-group, multicenter, three-cycle study evaluated three patches containing different ethinyl estradiol (EE) and levonorgestrel (LNG) doses. Serum levels of EE, LNG, sex hormone-binding globulin and progesterone were compared in 41 obese [body mass index (BMI) ≥30] and 75 nonobese (BMI <30) women. RESULTS: Suppression of ovulation during the luteal phase was dose dependent, with the highest dose (AG200-15) preventing progesterone increases in all women (cycles 2-3). In the follicular phase, the lowest-dose patch had the highest rate of increased progesterone in nonobese subjects. Progesterone levels ≥3.0 ng/mL in the follicular phase were more common in obese than nonobese women. CONCLUSIONS: AG200-15 suppresses ovulation in obese and nonobese women. All three patches found increased progesterone in the follicular phase, albeit more in obese versus nonobese women.

Ethinyl estradiol and levonorgestrel pharmacokinetics with a low-dose transdermal contraceptive delivery system, AG200-15: a randomized controlled trial.

BACKGROUND: This study evaluated the ethinyl estradiol (EE) and levonorgestrel (LNG) pharmacokinetic profiles of AG200-15, a transdermal contraceptive delivery system, compared with a combination oral contraceptive (COC) containing EE 35 mcg and norgestimate 250 mcg. STUDY DESIGN: A Phase 1, open-label, single-center study in 36 healthy women was conducted over three cycles with a randomized crossover design. After a run-in cycle of 21 days on and 7 days off with AG200-15, participants were randomized to receive one of two treatments: a 21/7-day cycle of AG200-15 either followed or preceded by one cycle of the COC. This trial is registered on ClinicalTrials.gov under the identifier NCT01243580. RESULTS: During the third week of AG200-15 use, mean (±standard deviation) maximum serum concentration (C(max)), area under the curve(0-168 h) and steady-state concentration (C(ss48-168 h)) for EE were 51.3 ± 17.3 pg/mL, 6.26 ± 2.46 ng h/mL and 35.7 ± 14.5 pg/mL, respectively; for LNG, the corresponding values were 2400 ± 1140 pg/mL, 317 ± 159 ng h/mL and 1847 ± 930 pg/mL, respectively. The AG200-15 EE C(max) was approximately 60% lower and the EE C(ss) was 15%-20% lower than those obtained with the COC. The calculated daily dose of AG200-15 was equivalent to a 30-mcg EE COC. The most common adverse events (AEs; >10%) in the AG200-15 group were headache, nausea and application-site irritation. All drug-related AEs were mild, and no serious AEs were reported. CONCLUSIONS: EE and LNG daily exposure during AG200-15 treatment was within the range reported for a low-dose COC. The daily EE dose with AG 200-15 was equivalent to a 30-mcg COC and was safe and well tolerated.

Pharmacokinetics, tolerability and cycle control of three transdermal contraceptive delivery systems containing different doses of ethinylestradiol and levonorgestrel.

BACKGROUND: The only available contraceptive patch, Ortho Evra®, delivers a relatively high dose of estrogen. MATERIALS AND METHODS: Three transdermal contraceptive delivery systems (TCDS) containing low doses of ethinylestradiol (EE) and levonorgestrel (LNG) were evaluated in two open-label randomized trials. In a phase 1, two-period, cross-over trial, AG200-12.5 and AG200LE were compared with a 150 µg LNG/30 µg EE oral contraceptive (OC) (Levlen®) in 39 women. In a phase 2, parallel-group, multicenter, three-cycle study, AG200LE, AG200-12.5 and a higher-dose formulation, AG200-15, were evaluated in 123 women. RESULTS: In Study 1, mean steady-state plasma concentrations (Css, pg/mL) for the TCDS were 17 pg/mL to 26 pg/mL for EE and 1117 pg/mL to 1505 pg/mL for LNG (for AG200LE and AG200-12.5 respectively). Maximum concentration (Cmax) and Css for both analytes were significantly lower than for Levlen. In both studies, the Css levels for EE and LNG in all groups were within the ranges reported for low-dose OCs. Cycle control for AG200-15, assessed by breakthrough bleeding and spotting episodes as well as number of days of unscheduled bleeding and/or spotting, was similar to that reported for low-dose OCs. Most adverse events were considered mild to moderate in intensity. The incidence of patches falling off was <2%. CONCLUSIONS: All three patches exhibited excellent safety and wearability profiles while maintaining plasma drug levels required for ovulation suppression and adequate cycle control. A slight increase in the EE dose in AG200-15 still places this TCDS within the range of low-dose OCs, with EE exposure much lower than reported for Ortho Evra. AG200-15 was selected for further testing in phase 3 studies.