Comparison of Cerebral Blood Flow in Regions Relevant to Cognition After Enzalutamide, Darolutamide, and Placebo in Healthy Volunteers: A Randomized Crossover Trial.

BACKGROUND: Off-target central nervous system (CNS) effects are associated with androgen receptor (AR)-targeting treatments for prostate cancer. Darolutamide is a structurally distinct AR inhibitor with low blood-brain barrier penetration. OBJECTIVE: We compared cerebral blood flow (CBF) in grey matter and specific regions related to cognition after darolutamide, enzalutamide, or placebo administration, using arterial spin-label magnetic resonance imaging (ASL-MRI). METHODS: This phase I, randomized, placebo-controlled, three-period crossover study administered single doses of darolutamide, enzalutamide, or placebo to 23 healthy males (aged 18-45 years) at 6-week intervals. ASL-MRI mapped CBF 4 h post-treatment. Treatments were compared using paired t-tests. RESULTS: Drug concentrations during scans confirmed similar unbound exposure of darolutamide and enzalutamide, with complete washout between treatments. A significant localized 5.2% (p = 0.01) and 5.9% (p < 0.001) CBF reduction in the temporo-occipital cortices was observed for enzalutamide versus placebo and versus darolutamide, respectively, with no significant differences for darolutamide versus placebo. Enzalutamide reduced CBF in all prespecified regions, with significant reductions versus placebo (3.9%, p = 0.045) and versus darolutamide (4.4%, p = 0.037) in the left and right dorsolateral prefrontal cortices, respectively. Darolutamide showed minimal changes in CBF versus placebo in cognition-relevant regions. CONCLUSIONS: Darolutamide did not significantly alter CBF, consistent with its low blood-brain barrier penetration and low risk of CNS-related adverse events. A significant reduction in CBF was observed with enzalutamide. These results may be relevant to cognitive function with early and extended use of second-generation AR inhibitors, and warrant further investigation in patients with prostate cancer. TRIAL REGISTRATION NUMBER: NCT03704519; date of registration: October 2018.

Androgens, or male sex hormones, bind to androgen receptors within prostate cells and can cause growth of prostate cancer. The treatment of prostate cancer often includes drugs that bind to androgen receptors, called androgen receptor inhibitors, keeping androgens from binding to the receptors and preventing prostate cancer growth. In clinical studies, these drugs may have adverse effects on the central nervous system, or brain, including dizziness, falls, and impaired thinking and problem solving. This study compared the effects of two androgen receptor inhibitors, darolutamide and enzalutamide, and placebo on blood flow in the brain. Blood flow was measured by a type of magnetic resonance imaging in healthy men after receiving a single dose of treatment. Blood flow in the brain was reduced by enzalutamide compared with both placebo and darolutamide. Darolutamide did not decrease brain blood flow. This lack of effect on brain blood flow is in line with preclinical studies that showed darolutamide's limited ability to cross the blood­brain barrier, which is the naturally occurring barrier that protects the brain from harmful substances. In clinical studies of patients with prostate cancer treated with darolutamide, adverse effects on the brain have occurred in similar proportions of patients receiving darolutamide and placebo. In contrast, enzalutamide treatment has an increased risk of adverse effects on the brain versus placebo. The results of this study provide information on the effects of these androgen receptor inhibitors on brain blood flow that may be related to their adverse effects on the brain and its functioning.

Clinical Pharmacokinetics of the Androgen Receptor Inhibitor Darolutamide in Healthy Subjects and Patients with Hepatic or Renal Impairment.

BACKGROUND: Darolutamide is a second-generation androgen receptor inhibitor approved for the treatment of nonmetastatic castration-resistant prostate cancer at a dosage of 600 mg orally twice daily. OBJECTIVE: We aimed to fully characterize the pharmacokinetic profile of darolutamide, its diastereomers, and its main active metabolite, keto-darolutamide. METHODS: Single-dose and multiple-dose pharmacokinetics of 14C-labeled and non-labeled darolutamide were evaluated in healthy subjects and patients with hepatic or renal impairment. RESULTS: Following darolutamide oral tablet administration, peak plasma concentrations were reached 4-6 h after dosing. Darolutamide elimination was characterized by a half-life of 13 h. Steady state was reached after approximately 2 days of twice-daily dosing. Pharmacokinetics of the diastereomers and keto-darolutamide followed similar trends to the parent compound. Darolutamide absorption from the tablet was lower than from the oral solution; tablet absolute bioavailability was ~30% in the fasted state but improved to 60-75% when given with food. The unbound fraction of darolutamide in plasma was 7.8%. The administered 1:1 ratio of the diastereomers (S,R)-darolutamide and (S,S)-darolutamide changed to ~1:6 in plasma following multiple dosing. Similar exposure and diastereomer ratios after single and multiple dosing indicate time-independent (no autoinduction) linear pharmacokinetics. Darolutamide exposure increased in patients with moderate hepatic or severe renal impairment vs healthy subjects; dose adaptation at treatment initiation should be considered in these patients. CONCLUSIONS: Darolutamide 600 mg twice daily demonstrates predictable linear pharmacokinetics and sustainably high plasma concentrations, suggesting the potential for constant inhibition of the androgen receptor signaling pathway. CLINICAL TRIALS REGISTRATION: NCT02418650, NCT02894385, NCT02671097.

Metabolism and Mass Balance of the Novel Nonsteroidal Androgen Receptor Inhibitor Darolutamide in Humans.

The biotransformation and excretion of darolutamide were investigated in a phase I study. Six healthy male volunteers received a single dose of 300 mg 14C-darolutamide as an oral solution in the fasted state. Plasma, urine, and feces samples were analyzed for mass balance evaluation by liquid scintillation counting (LSC). Metabolite profiling and identification were determined using liquid chromatography mass-spectrometry with off-line radioactivity detection using LSC. Complete mass balance was achieved, with mean radioactivity recovery of 95.9% within 168 hours (63.4% in urine, 32.4% in feces). The administered 1:1 ratio of (S,R)- and (S,S)-darolutamide changed to approximately 1:5, respectively, in plasma. Darolutamide and the oxidation product, keto-darolutamide, were the only components quantifiable by LSC in plasma, accounting for 87.4% of total radioactivity, with a 2.1-fold higher plasma exposure for keto-darolutamide. Aside from darolutamide, the most prominent metabolites in urine were O-glucoronide (M-7a/b) and N-glucuronide (M-15a/b), as well as pyrazole sulfates (M-29, M-24) and glucuronides (M-21, M-22) resulting from oxidative cleavage of the parent. The darolutamide diastereomers were mainly detected in feces. In vitro assays showed that darolutamide metabolism involves a complex interplay between oxidation and reduction, as well as glucuronidation. Interconversion of the diastereomers involves oxidation to keto-darolutamide, primarily mediated by CYP3A4, followed by reduction predominantly catalyzed by cytosolic reductase(s), with aldo-keto reductase 1C3 playing the major role. The latter reaction showed stereoselectivity with preferential formation of (S,S)-darolutamide. SIGNIFICANCE STATEMENT: The metabolism and excretion of darolutamide in humans revealed that oxidation (CYP3A4) and glucuronidation (UGT1A9, UGT1A1) were the main metabolic routes of elimination. Direct excretion also contributed to overall clearance. The two pharmacologically equipotent diastereomers of darolutamide interconvert primarily via oxidation to the active metabolite keto-darolutamide, followed by reduction predominantly by cytosolic reductase(s). The latter reaction showed stereoselectivity with preferential formation of (S,S)-darolutamide. Data indicate a low drug-drug interaction potential of darolutamide with inducers or inhibitors of metabolizing enzymes.

Pharmacokinetics of Darolutamide, its Diastereomers and Active Metabolite in the Mouse: Response to Saini NK et al. (2020).

BACKGROUND: Saini et al. recently investigated the pharmacokinetics of darolutamide and its diastereomers in vitro and in vivo in Balb/c mice, reporting higher levels of (S,S)-darolutamide than (S,R)-darolutamide following intravenous or oral dosing, and interconversion of (S,R)-darolutamide to (S,S)-darolutamide. OBJECTIVE: To present our in vitro and in vivo studies of darolutamide pharmacokinetics in mice, which contrast with the findings of Saini et al. Methods: Nude male Balb/c mice were orally dosed for 7 days with 25, 50, or 100 mg/kg of darolutamide twice daily. Pharmacokinetic parameters in plasma and tissue samples were assessed by liquid chromatography-tandem mass spectrometry. Metabolism and interconversion of darolutamide and its diastereomers were investigated in cryopreserved Balb/c mouse hepatocytes. Protein binding was determined in plasma samples by equilibrium dialysis. RESULTS: On day 7, Cmax was reached 30 min after the last dose. Rapid formation and greater exposure of keto-darolutamide versus darolutamide were observed. Plasma exposure of (S,R)-darolutamide was 3-5-fold higher than that of (S,S)-darolutamide. The fraction of unbound keto-darolutamide was almost 6-fold lower than for darolutamide. In mouse hepatocytes, the conversion of (S,S)- to (S,R)-darolutamide was observed, but the conversion of (S,R)- to (S,S)-darolutamide was not detectable. Back-formation of keto-darolutamide to both diastereomers occurred at low levels. CONCLUSION: The darolutamide diastereomer ratio changes upon administration in mice and other species due to interconversion through keto-darolutamide. This is not considered clinically relevant since both diastereomers and keto- darolutamide are pharmacologically similar in vitro. Based on the high protein binding of keto-darolutamide, its contribution in vivo in humans is considered low.

Evaluation of Clinically Relevant Drug-Drug Interactions and Population Pharmacokinetics of Darolutamide in Patients with Nonmetastatic Castration-Resistant Prostate Cancer: Results of Pre-Specified and Post Hoc Analyses of the Phase III ARAMIS Trial.

BACKGROUND: Darolutamide, an androgen receptor antagonist with a distinct molecular structure, significantly prolonged metastasis-free survival versus placebo in the phase III ARAMIS study in men with nonmetastatic castration-resistant prostate cancer (nmCRPC). In this population, polypharmacy for age-related comorbidities is common and may increase drug-drug interaction (DDI) risks. Preclinical/phase I study data suggest darolutamide has a low DDI potential-other than breast cancer resistance protein/organic anion transporter protein substrates (e.g., statins), no clinically relevant effect on comedications is expected. OBJECTIVE: Our objective was to evaluate the effect of commonly administered drugs on the pharmacokinetics of darolutamide and the effect of comedications potentially affected by darolutamide on safety in patients with nmCRPC. PATIENTS AND METHODS: Comorbidities and comedication use in the 1509 ARAMIS participants treated with darolutamide 600 mg twice daily or placebo were assessed. A population pharmacokinetic analysis evaluated whether comedications affected the pharmacokinetics of darolutamide in a subset of 388 patients. A subgroup analysis of adverse events (AEs) in statin users versus nonusers was conducted. RESULTS: Most participants (median age 74 years) had at least one comorbidity (98.4% in both arms) and used at least one comedication (98.7% with darolutamide vs. 98.0% with placebo); these were similar across study arms. Despite frequent use of comedications with DDI potential, no significant effects on darolutamide pharmacokinetics were identified. Comedications included lipid-modifying agents (34.5%), ß-blockers (29.7%), antithrombotics (42.8%), and systemic antibiotics (26.9%). AE incidence was similar across study arms in statin users and nonusers. Study limitations include the small sample size for sub-analyses. CONCLUSIONS: These analyses suggest the pharmacokinetic profile of darolutamide is not affected by a number of commonly administered drugs in patients with nmCRPC. Although pharmacokinetic data have indicated that darolutamide has the potential to interact with rosuvastatin, used to assess DDI in these studies, this finding did not seem to translate into increased AEs due to statin use in the ARAMIS trial. Clinicaltrials.gov identifier: NCT02200614.

BACKGROUND: Darolutamide is a medicine used to treat men with prostate cancer that has not spread to other parts of the body (nonmetastatic). Often, these patients are taking other medicines for common age-related illnesses. Taking more than one medicine at the same time increases the chances of what is known as drug­drug interactions. Drug­drug interactions can decrease how well the medicines work or may sometimes increase side effects. STUDY AIM: To test for possible drug­drug interactions in men with prostate cancer who take darolutamide alongside other medicines. STUDY PARTICIPANTS: Men with nonmetastatic prostate cancer who were being treated with a medicine that lowers testosterone, a chemical in the body that causes prostate cancer tumors to grow. Participants took two darolutamide 300 mg tablets, or an inactive placebo, twice a day. WHAT DID THE RESEARCHERS MEASURE?: The researchers documented the number of medicines taken by each participant and the number of other medical conditions that they had. Tests were done to find out whether other medicines affected the way that darolutamide works in the body and whether patients taking darolutamide alongside other medicines experienced more side effects. RESULTS: As would be expected, based on the typical age of patients with prostate cancer, more than 90% of participants in this study used medicines other than darolutamide to manage common age-related illnesses or medical conditions. Taking medicines alongside darolutamide did not impact how darolutamide worked in the body and did not increase the number of side effects experienced by patients. Darolutamide is known to interact with rosuvastatin, a cholesterol-lowering drug. However, in this study, there was no overall increase in side effects among darolutamide-treated patients who took this type of drug compared with in those who did not. CONCLUSION: In this study of patients with nonmetastatic prostate cancer, limited drug­drug interactions were seen when taking darolutamide alongside other medicines given to these patients to manage age-related medical conditions.

Drug-Drug Interaction Potential of Darolutamide: In Vitro and Clinical Studies.

BACKGROUND AND OBJECTIVES: Darolutamide is a novel androgen receptor (AR) antagonist approved for the treatment of nonmetastatic castration-resistant prostate cancer (nmCRPC). Accordingly, the drug-drug interaction (DDI) potential of darolutamide was investigated in both nonclinical and clinical studies. METHODS: In vitro studies were performed to determine the potential for darolutamide to be a substrate, inducer or inhibitor for cytochrome P450 (CYP) isoforms, other metabolizing enzymes and drug transporters. A phase I drug-interaction study in healthy volunteers evaluated the impact of co-administering rifampicin [CYP3A4 and P-glycoprotein (P-gp) inducer] and itraconazole [CYP3A4, P-gp and breast cancer resistance protein (BCRP) inhibitor] on the pharmacokinetics of darolutamide. Two further phase I studies assessed the impact of co-administering oral darolutamide on the pharmacokinetics of midazolam (sensitive CYP3A4 substrate) and dabigatran etexilate (P-gp substrate) and the impact on the pharmacokinetics of co-administered rosuvastatin [a substrate for BCRP, organic anion-transporting polypeptide (OATP)1B1, OATP1B3 and organic anion transporter (OAT)3]. RESULTS: In vitro, darolutamide was predominantly metabolized via oxidative biotransformation catalyzed by CYP3A4 and was identified as a substrate for P-gp and BCRP. The enzymatic activity of nine CYP isoforms was not inhibited or slightly inhibited in vitro with darolutamide, and a rank order and mechanistic static assessment indicated that risk of clinically relevant DDIs via CYP inhibition is very low. In vitro, darolutamide exhibited no relevant induction of CYP1A2 or CYP2B6 activity. Inhibition of BCRP-, P-gp-, OAT3-, MATE1-, MATE2-K-, OATP1B1- and OATP1B3-mediated transport was observed in vitro. Phase I data showed that darolutamide exposure increased 1.75-fold with co-administered itraconazole and decreased by 72% with rifampicin. Co-administration of darolutamide with CYP3A4/P-gp substrates showed no effect or only minor effects. Rosuvastatin exposure increased 5.2-fold with darolutamide because of BCRP and probably also OATPB1/OATPB3 inhibition. CONCLUSIONS: Darolutamide has a low potential for clinically relevant DDIs with drugs that are substrates for CYP or P-gp; increased exposure of BCRP and probably OATP substrates was the main interaction of note.

Phase 1 study of darolutamide (ODM-201): a new-generation androgen receptor antagonist, in Japanese patients with metastatic castration-resistant prostate cancer.

PURPOSE: This trial assessed the safety, pharmacokinetics, and efficacy of darolutamide (ODM-201), a new-generation nonsteroidal androgen receptor antagonist, in Japanese patients with metastatic castration-resistant prostate cancer (mCRPC). METHODS: In this open-label, nonrandomized, two-cohort, dose-escalating phase 1 study, Japanese patients with mCRPC were enrolled after a screening period. In the single-dose period (≈1 week), darolutamide was administered at 300 mg (Cohort 1) or 600 mg (Cohort 2) on day -5 (fasting state) and day -2 (fed condition). In the subsequent multiple-dose period (fed condition), patients received darolutamide 300 mg twice daily (Cohort 1) or 600 mg twice daily (Cohort 2) for 12 weeks. Primary endpoints: evaluate safety and pharmacokinetics of darolutamide. RESULTS: Of 12 patients enrolled, 9 received darolutamide (Cohort 1, n = 3; Cohort 2, n = 6). All 9 patients experienced ≥1 treatment-emergent adverse event (TEAE; majority Grade 1/2). Incidence of drug-related TEAEs (DR-TEAEs) was 44% (all grades; n = 4); most common DR-TEAE was decreased appetite (22%), and 1 serious DR-TEAE (Grade 3 nausea) was observed. No Grade ≥4 DR-TEAEs or new safety signals were observed. C max and AUC (0-t last) were dose-dependent; pharmacokinetics of each dose appeared to be linear over time. Prostate-specific antigen response was observed in 11% (1/9) of patients. Compared with fasting status, geometric mean C max increased 2.5-fold after 300 mg and 2.8-fold after 600 mg; geometric mean AUC (0-t last) increased 2.5-fold after both doses under fed conditions. CONCLUSIONS: Darolutamide was well tolerated at the examined doses in Japanese patients with mCRPC, without differences in safety and pharmacokinetics relative to Western patients.

Pharmacokinetics of single dose radium-223 dichloride (BAY 88-8223) in Japanese patients with castration-resistant prostate cancer and bone metastases.

OBJECTIVE: This open-label, non-randomized, phase I study examined the pharmacokinetics (PK) and radiation dosimetry of a single dose of radium-223 in Japanese patients with castration-resistant prostate cancer (CRPC) and bone metastases. METHODS: Six male Japanese patients (mean age 72.5 years, range 65-79 years) with histologically or cytologically confirmed stage IV adenocarcinoma of the prostate were recruited. A single IV dose of radium-223 was delivered intravenously (IV) via slow bolus over a 2-5 min period: Cohort 1 received 50 kBq/kg and Cohort 2 received 100 kBq/kg. RESULTS: Following IV injection, radium-223 was rapidly eliminated from the blood in a multi-phasic manner. The fraction of the injected activity of radium-223 retained in the whole body 24 h following injection was 85 %. Biodistribution results showed initial bone uptake was 52 % (range 41-57 %). The maximum activity of radium-223 in the bone was observed within 2 h of dosing. Activity of radium-223 passed through the small intestine within 24 h. No activity was detected in other organs. The major radiation dose from radium-223 was found in osteogenic cells; calculated absorbed doses in osteogenic cells and in the red marrow were 0.76 Gy/MBq and 0.09 Gy/MBq, respectively. CONCLUSIONS: In Japanese patients with CRPC and bone metastases, radium-223 (IV) achieved maximum activity in the bone rapidly and passed through the intestine within 24 h, without signs of activity in other organs. The PK profile and absorbed radiation dose in organs and tissues in Japanese patients were similar to data from non-Japanese patients. Trial registration identification: NCT01565746.

Pharmacokinetics and adhesion of a transdermal patch containing ethinyl estradiol and gestodene under conditions of heat, humidity, and exercise: A single-center, open-label, randomized, crossover study.

In this open-label, randomized study, 36 women (18-45 years) applied an ethinyl estradiol/gestodene contraceptive patch once-weekly for 3 weeks followed by a 1-week, patch-free interval, in 3 treatment periods. The primary objective was to evaluate the pharmacokinetics of ethinyl estradiol and gestodene under conditions of heat, humidity, and exercise. The secondary objective was to evaluate patch adhesion under the same conditions. Weeks 1 and 2 of each period comprised "standardized normal activity" (SNA); in week 3, SNA continued or women used a sauna, whirlpool, swimming pool, or performed an exercise combination. Thirty-one women completed the study; 23 yielded evaluable pharmacokinetic data. Analyses were exploratory and conducted using an analysis of variance. Area under the concentration-time curve from 0 to 168 hours (AUC0-168 ) for gestodene and ethinyl estradiol during sauna, swimming, and whirlpool was equivalent to previous SNA recordings. For exercise combination, the gestodene AUC0-168 was 12% lower compared with SNA, albeit not considered clinically relevant. Two women lost a total of 3 patches during sporting activities; other detachments during this week were not correlated with sporting activity. Overall, hormone delivery using the ethinyl estradiol/gestodene patch under conditions of heat, humidity, and exercise corresponded to delivery under normal conditions.

Pharmacokinetic drug-drug interaction between ethinyl estradiol and gestodene, administered as a transdermal fertility control patch, and two CYP3A4 inhibitors and a CYP3A4 substrate.

Pharmacokinetic (PK) interactions between the cytochrome P450 3A4 (CYP3A4) pathway and transdermally administered ethinyl estradiol (EE) and gestodene (GSD) were investigated. This paper reports the findings of three open-label, intra-individual, one-way crossover, Phase I trials. In two studies, women used a novel contraceptive patch for 3 weeks during two 4-week study periods; in the second period, the CYP3A4 inhibitors erythromycin (Study 1) or ketoconazole (Study 2) were administered concurrently. In a third study, women received single doses of the CYP3A4 model substrate midazolam, alone and after 3 weeks of concurrent patch application. In each period, the EE/GSD patch (delivering low EE and GSD doses resulting in the same systemic exposure as a combined oral contraceptive containing 0.02 mg EE and 0.06 mg GSD) was applied once weekly for 3 weeks, with one patch-free week. Erythromycin, ketoconazole, and midazolam were administered orally. Main outcome measures were area under the curves (AUCs) and maximum plasma concentration (C max) of EE, and total and unbound GSD (Studies 1 and 2). AUC and C max of midazolam (Study 3). Co-administration of CYP3A4 inhibitors did not affect EE metabolism, and had only weak effects on the PK of total and unbound GSD. The patch had no clinically relevant effect on metabolism of the CYP3A4 substrate midazolam.

Pharmacokinetic overview of ethinyl estradiol dose and bioavailability using two transdermal contraceptive systems and a standard combined oral contraceptive.

OBJECTIVE: To determine the relative bioavailability of ethinyl estradiol (EE) and gestodene (GSD) after application of a novel transdermal contraceptive patch vs. a standard combined oral contraceptive (COC) pill (study 1), and to evaluate the pharmacokinetics (PK) of EE after application of the EE/GSD patch compared with an EE/norelgestromin (NGMN) patch (study 2). MATERIALS: Participants were healthy, nonobese women aged 18 - 45 years (study 1) or 18 - 35 years (study 2). Compositions of study treatments were as follows: 0.55 mg EE/2.1 mg GSD (EE/GSD patch); 0.02 mg EE/0.075 mg GSD (standard COC); 0.6 mg EE/6 mg NGMN (EE/NGMN patch). METHODS: In study 1, which consisted of 3 treatment periods (each followed by 7 patch- or pill-free days), treatments were administered in one of two randomized orders: either P-M-E (EE/GSD patch (P) every 7 days for 28 days → COC (M) once-daily for 21 days → two 7-day patch-wearing periods followed by one 10-day patch-wearing phase (E)), or the same treatments administered in sequence M-P-E. For study 2, participants received either the EE/GSD patch or EE/NGMN patch for seven treatment cycles (one patch per week for 3 weeks followed by a 7-day patch-free interval). RESULTS: In study 1, average daily exposure to EE was similar for treatments P and M; the mean daily area under the concentration-time curve (AUC) ratio of treatment P vs. treatment M for EE was 1.06 (90% confidence interval (CI): 0.964 - 1.16), indicating average daily delivery similar to oral administration of 0.019 - 0.023 mg EE. For unbound GSD, average daily exposure was lower for treatment P vs. treatment M. The mean AUC ratio of treatment P vs. treatment M for unbound GSD was 0.820 (90% CI: 0.760 - 0.885), indicating average daily delivery from the patch of 0.057 - 0.066 mg GSD. Prolonged patch wearing did not result in a distinct decline in GSD and EE serum concentrations. In study 2, AUC at steady state (AUC0-168,ss), average steady-state serum concentration, and maximum steady-state serum concentration for EE was 2.0 - 2.7-fold higher for the EE/NGMN patch vs. the EE/GSD patch. The EE/GSD patch was well tolerated in both studies. CONCLUSIONS: Based on the 90% CI of the AUC ratio of oral treatment vs. patch application for unbound GSD and EE, the daily doses of GSD and EE released from the EE/GSD patch over the 7-day application period provided the same systemic exposure as those recorded after daily oral administration of a COC containing 0.02 mg EE and 0.06 mg GSD. The EE/GSD patch showed reduced EE exposure compared with the EE/NGMN patch. Together with its good tolerability, these properties support the EE/GSD patch as an effective and well-tolerated alternative to available transdermal and oral contraceptives.

Implications of different application sites on the bioavailability of a transdermal contraceptive patch containing ethinyl estradiol and gestodene: an open-label, randomized, crossover study.

OBJECTIVES: A novel once-a-week contraceptive patch delivers the same systemic exposure seen with a combined oral contraceptive pill containing 0.02 mg ethinyl estradiol (EE) and 0.06 mg gestodene (GSD). This study evaluated the relative bioavailability of EE and GSD after application of this patch to three different sites. METHODS: In this phase I, open-label, randomized, intra-individual comparison, crossover study, 43 women (aged 18 - 45 years) were randomized to one of six treatment sequences. Patches were applied to two test sites (buttocks and outer, upper arm) and one comparator site (lower abdomen). In each treatment period, four patches were worn for 7 days each, followed by a 7-day, patch-free interval. The primary objective was to investigate the relative bioavailability of transdermally administered EE and GSD between test and comparator sites using the primary variable area under the concentration- time curve (AUC(0-168)) during week 4 of each period. RESULTS: Of the 43 women who were randomized, 43 were included in the set for safety evaluation and 40 were included in the set for pharmacokinetic (PK) analysis. Three subjects were excluded from the PK analysis as they failed to complete the study. AUC(0-168) for EE and GSD were equal when the patch was applied to buttocks or abdomen (AUC(0-168) ratios: EE, 1.07 (94% confidence interval, CI: 0.994 - 1.16); GSD, 1.02 (94% CI: 0.946 - 1.10)). Relative bioavailabilities for EE and GSD were 31% and 24% higher, respectively, for arm vs. abdomen. AUC(0-168) 94% CI for the arm/abdomen ratio exceeded the pre-defined bioequivalence range of 80 - 125% (EE: 1.21 - 1.42; GSD: 1.15 - 1.34). Other PK parameters were correspondingly higher for arm vs. buttocks or abdomen. Patch adhesion and tolerability were good, with no relevant differences between sites. CONCLUSION: Differences in systemic EE/GSD exposure following patch application to the outer, upper arm vs. lower abdomen and buttocks are unlikely to be clinically relevant, and there were no relevant safety concerns.

Pharmacokinetics of two low-dose levonorgestrel-releasing intrauterine systems and effects on ovulation rate and cervical function: pooled analyses of phase II and III studies.

OBJECTIVE: To assess the pharmacokinetics and pharmacodynamics of levonorgestrel intrauterine system (LNG-IUS) 13.5 mg and LNG-IUS 19.5 mg (total content). DESIGN: Pooled pharmacokinetic and pharmacodynamic analyses of phase II and III studies. SETTING: Randomized, open-label, multicenter studies. PATIENT(S): Nulliparous and parous women. INTERVENTION(S): Levonorgestrel intrauterine system 13.5 mg, LNG-IUS 19.5 mg, or LNG-IUS 20 µg/24 h (total content 52 mg). MAIN OUTCOME MEASURE(S): Pharmacokinetics of LNG, ovulation rate, cervical function, and endometrium effects. RESULT(S): The in vivo LNG release rate of LNG-IUS 13.5 mg was approximately 14 µg/24 h after 24 days, declining progressively to 5 µg/24 h after 3 years. The average LNG serum concentration over 3 years of use was 74.3 ng/L, 114 ng/L, and 218 ng/L for LNG-IUS 13.5 mg, LNG-IUS 19.5 mg, and LNG-IUS 20 µg/24 h, respectively. All treatments showed very similar progestogenic effects on cervical mucus, with low and similar cervical scores throughout treatment. Ovulation was observed in the majority of women in all groups where assessment was possible, although there was a lower incidence of anovulation with LNG-IUS 13.5 mg and LNG-IUS 19.5 mg compared with LNG-IUS 20 µg/24 h. The progestogenic effect on the endometrium was marked in all three LNG-IUS groups. CONCLUSION(S): Levonorgestrel intrauterine system 13.5 mg and LNG-IUS 19.5 mg result in alower systemic exposure to LNG, lower incidence of anovulation, and similar progestin impact on the endometrium and cervical function compared with LNG-IUS 20 µg/24 h.

Pharmacokinetics of continuous once-a-week combination 17ß-Estradiol/Low- or high-dose levonorgestrel transdermal delivery systems in postmenopausal women.

Two open-label, randomized, two-period, crossover studies were performed to determine the safety, delivery rates, and pharmacokinetic properties of a combination estradiol (E2)/levonorgestrel (LNG) transdermal delivery system (TDS). Study 1 enrolled 24 postmenopausal women who received a single TDS containing 4.4 mg E2 and 1.39 mg of LNG (E2/LNG Low) or E2 0.050 mg/24 hours TDS and 0.090 mg LNG oral tablet. Study 2 enrolled 44 postmenopausal women who received either E2/LNG Low or TDS containing 4.4 mg E2 and 2.75 mg LNG (E2/LNG High) weekly for a period of 4 weeks. E2, estrone (E1), LNG, and sex hormone-binding globulin (SHBG) serum concentrations were determined. Overall, both E2/LNG TDS were well tolerated and had excellent adhesion properties. The average daily delivery for E2/LNG Low was 0.045 mg for E2 and 0.0132 mg for LNG. Following weekly delivery of E2/LNG Low or High for 4 weeks, the combination of E2 with two different strengths of LNG did not alter the pharmacokinetic profile of E2. SHBG, total cholesterol, and triglycerides concentrations significantly decreased compared to baseline. Both E2/LNG Low and High TDSs were well tolerated and provided continuous drug delivery over 7 days supporting the benefits of the transdermal route of administration in optimally delivering hormonal therapy.

Ovulation-inhibiting effects of dienogest in a randomized, dose-controlled pharmacodynamic trial of healthy women.

Dienogest offers pharmacological advantages for the effective treatment of endometriosis and for use in contraception and hormone replacement therapy. This pharmacodynamic study investigated the ovulation-inhibiting effects of dienogest monotherapy in healthy women. Dienogest was administered at 0.5, 1, 2, or 3 mg daily for up to 72 days to women aged 18 to 35 years (n = 102). Ovarian activity was assessed pretreatment and during 2 treatment periods (days 0-36 and days 37-72) by the Hoogland score, based on follicle size and serum estradiol and progesterone levels. Additional hormonal parameters and endometrial thickness were assessed. Hoogland scoring indicated ovulation in all women pretreatment, decreasing to 3 of 21, 1 of 23, 0 of 20, and 0 of 23 women in the 0.5-, 1-, 2-, and 3-mg groups, respectively (per-protocol set). Maximum serum estradiol concentrations were similar to pretreatment levels in the 0.5- or 1-mg group and decreased moderately (within physiologic levels) in the 2- or 3-mg group. Endometrial thickness was reduced by all dienogest doses. Hormonal changes during follow-up indicated resumption of ovulation in most women, shortly after treatment cessation. Dienogest ≥2 mg daily provides moderate suppression of estradiol production and reliable ovulation inhibition, which reverses rapidly after treatment cessation.

Simultaneous estradiol and levonorgestrel transdermal delivery from a 7-day patch: in vitro and in vivo drug deliveries of three formulations.

A new drug-in-adhesive transdermal patch was developed to deliver both estradiol and levonorgestrel through the skin over a 7-day period, but at different rates. This report elucidates the in vitro and in vivo biopharmaceutical studies that were necessary during the development of this product. Three test patches had to be manufactured, all delivering estradiol at the same rate, but delivering levonorgestrel at three different rates so that a levonorgestrel dose response could be studied in the clinic. An in vitro hairless mouse skin model (HMS) using modified Franz diffusion cells was used to select the test products delivering levonorgestrel in the order of 1:2:3. HMS experiments also demonstrated that the presence of estradiol did not affect the flux of levonorgestrel. Two in vivo studies in postmenopausal women showed that at steady state (four weeks of once-weekly dosing) the three test products all delivered estradiol at comparable rates. Similarly, the levonorgestrel deliveries for the three test products were in the order expected. The target fluxes of both drugs were achieved in these three test products by varying the drug loads and patch size. That this approach was successful is evidence of the value of using the HMS penetration experiments in transdermal product development and should provide useful insights for other formulations having to develop complex systems. One of the test products is now marketed as Climara Pro.