Intra-individual Dose Escalation of Abiraterone According to Its Plasma Exposure in Patients with Progressive Metastatic Castration-Resistant Prostate Cancer: Results of the OPTIMABI Trial.

BACKGROUND AND OBJECTIVE: Trough abiraterone concentration (ABI Cmin) of 8.4 ng/mL has been identified as an appropriate efficacy threshold in patients treated for metastatic castration-resistant prostate cancer (mCRPC). The aim of the phase II OPTIMABI study was to evaluate the efficacy of pharmacokinetics (PK)-guided dose escalation of abiraterone acetate (AA) in underexposed patients with mCRPC with early tumour progression. METHODS: This multicentre, non-randomised study consisted of two sequential steps. In step 1, all patients started treatment with 1000 mg of AA once daily. Abiraterone Cmin was measured 22-26 h after the last dose intake each month during the first 12 weeks of treatment. In step 2, underexposed patients (Cmin < 8.4 ng/mL) with tumour progression within the first 6 months of treatment were enrolled and received AA 1000 mg twice daily. The primary endpoint was the rate of non-progression at 12 weeks after the dose doubling. During step 1, adherence to ABI treatment was assessed using the Girerd self-reported questionnaire. A post-hoc analysis of pharmacokinetic (PK) data was conducted using Bayesian estimation of Cmin from samples collected outside the sampling guidelines (22-26 h). RESULTS: In the intention-to-treat analysis (ITT), 81 patients were included in step 1. In all, 21 (26%) patients were underexposed in step 1, and 8 of them (38%) experienced tumour progression within the first 6 months. A total of 71 patients (88%) completed the Girerd self-reported questionnaire. Of the patients, 62% had a score of 0, and 38% had a score of 1 or 2 (minimal compliance failure), without a significant difference in mean ABI Cmin in the two groups. Four patients were enrolled in step 2, and all reached the exposure target (Cmin > 8.4 ng/mL) after doubling the dose, but none met the primary endpoint. In the post-hoc analysis of PK data, 32 patients (39%) were underexposed, and ABI Cmin was independently associated with worse progression-free survival [hazard ratio (HR) 2.50, 95% confidence interval (CI) 1.07-5.81; p = 0.03], in contrast to the ITT analysis. CONCLUSION: The ITT and per-protocol analyses showed no statistical association between ABI underexposure and an increased risk of early tumour progression in patients with mCRPC, while the Bayesian estimator showed an association. However, other strategies than dose escalation at the time of progression need to be evaluated. Treatment adherence appeared to be uniformly good in the present study. Finally, the use of a Bayesian approach to recover samples collected outside the predefined blood collection time window could benefit the conduct of clinical trials based on drug monitoring. OPTIMABI trial is registered as National Clinical Trial number NCT03458247, with the EudraCT number 2017-000560-15).

Evaluation of adherence to abiraterone therapy in prostate cancer patients based on a population pharmacokinetic model.

AIMS: Abiraterone treatment requires regular drug intake under fasting conditions due to pronounced food effect, which may impact patient adherence. The aim of this prospective study was to evaluate adherence to abiraterone treatment in patients with prostate cancer. To achieve this aim, an abiraterone population pharmacokinetic model was developed and patients' adherence has been estimated by comparison of measured levels of abiraterone with population model-based simulations. METHODS: A total of 1469 abiraterone plasma levels from 83 healthy volunteers collected in a bioequivalence study were analysed using a nonlinear mixed-effects model. Monte Carlo simulation was used to describe the theoretical distribution of abiraterone pharmacokinetic profiles at a dose of 1000 mg once daily. Adherence of 36 prostate cancer patients treated with abiraterone was then evaluated by comparing the real abiraterone concentration measured in each patient during follow-up visit with the theoretical distribution of profiles based on simulations. Patients whose abiraterone levels were ˂5th or ˃95th percentile of the distribution of simulated profiles were considered to be non-adherent. RESULTS: Based on this evaluation, 13 patients (36%) have been classified as non-adherent. We observed significant association (P = .0361) between richness of the breakfast and rate of non-adherence. Adherent patients reported significantly better overall condition in self-assessments (P = .0384). A trend towards a higher occurrence of adverse effects in non-adherent patients was observed. CONCLUSIONS: We developed an abiraterone population pharmacokinetic model and proposed an advanced approach to medical adherence evaluation. Due to the need for administration under fasting conditions, abiraterone therapy is associated with a relatively high rate of non-adherence.

Effect of food and polymorphisms in SLCO2B1, CYP3A4 and UGT1A4 on pharmacokinetics of abiraterone and its metabolites in Chinese volunteers.

AIMS: Abiraterone acetate, a prodrug of abiraterone (ABI), provides an efficient therapeutic option for metastatic castration-resistant prostate cancer patients. ABI undergoes extensive metabolism in vivo and is transformed into active metabolites Δ4 -abiraterone and 3-keto-5α-abiraterone as well as inactive metabolites abiraterone sulfate and abiraterone N-oxide sulfate. We aimed to examine the effect of polymorphisms in SLCO2B1, CYP3A4 and UGT1A4 on the pharmacokinetics of ABI and its metabolites. METHODS: In this study, 81 healthy Chinese subjects were enrolled and divided into 2 groups for fasted (n = 45) and fed (n = 36) studies. Plasma samples were collected after administering a 250 mg abiraterone acetate tablet followed by liquid chromatography-tandem mass spectrometry analysis. Genotyping was performed on a MassARRAY system. The association between SLCO2B1, CYP3A4, UGT1A4 genotype and pharmacokinetic parameters of ABI and its metabolites was assessed. RESULTS: Food effect study demonstrated high fat meal remarkedly increased systemic exposure of ABI and its metabolites. The geometric mean ratio and 90% confidence interval of area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration (AUC0-t ) and maximum plasma concentration (Cmax ) of ABI in fed state vs. fasted state were 351.64% (286.86%-431.04%) and 478.45% (390.01%-586.94%), respectively, while the corresponding results were ranging from 145.11% to 269.42% and 150.10% to 478.45% for AUC0-t and Cmax of ABI metabolites in fed state vs. fasted state, respectively. The SLCO2B1 rs1077858 had a significant influence on AUC0-t and Cmax , while 7 other SLCO2B1 variants prolonged half-life of ABI under both fasted and fed conditions. As for ABI metabolites, the systemic exposure of Δ4 -abiraterone, abiraterone sulfate and abiraterone N-oxide sulfate as well as the elimination of 3-keto-5α-abiraterone were significantly affected by SLCO2B1 polymorphisms. Polymorphisms in CYP3A4 and UGT1A4 did not significantly affect pharmacokinetics of ABI and its metabolites. CONCLUSION: Polymorphisms in SLCO2B1 were significantly related to the pharmacokinetic variability of ABI and its metabolites under both fasted and fed conditions.

The effect of drug loading on the properties of abiraterone-hydroxypropyl beta cyclodextrin solid dispersions processed by solvent free KinetiSol® technology.

Abiraterone is a poorly water-soluble drug used in the treatment of prostate cancer. In our previous study, we reported that KinetiSol® processed solid dispersions (KSDs) based on hydroxypropyl ß-cyclodextrin (HPBCD) showed improved dissolution and pharmacokinetics of abiraterone. However, the nature of abiraterone-HPBCD interaction within the KSDs or the effect of drug loading on the physicochemical properties and in vivo performance of HPBCD-based KSDs remain largely unknown. We hypothesize that KinetiSol technology can prepare abiraterone-HPBCD complexes within KSDs and that increasing the drug loading beyond an optimal point reduces the in vitro and in vivo performance of these KSDs. To confirm our hypothesis, we developed KSDs with 10-50% w/w drug loading and analyzed them using X-ray diffractometry and modulated differential scanning calorimetry. We found that KSDs containing 10-30% drug were amorphous. Interestingly, two-dimensional solid-state nuclear magnetic resonance and Raman spectroscopy indicated that the abiraterone-HPBCD complexes were formed. At elevated temperatures, the 10% and 20% drug-loaded KSDs were physically stable, while the 30% drug-loaded KSD showed recrystallization of abiraterone. In vitro dissolution and in vivo pharmacokinetic performances improved as the drug loading decreased; we attribute this to increased noncovalent interactions between abiraterone and HPBCD at lower drug loadings. Overall, the 10% drug loaded KSD showed a dissolution enhancement of 15.7-fold compared to crystalline abiraterone, and bioavailability enhancement of 3.9-fold compared to the commercial abiraterone acetate tablet Zytiga®. This study is first to confirm that KinetiSol, a high-energy, solvent-free technology, is capable of forming abiraterone-HPBCD complexes. Furthermore, in terms of in vitro and in vivo performance, a 10% drug load is optimal.

A quick UPLC-MS/MS method for therapeutic drug monitoring of abiraterone and delta(4)-abiraterone in human plasma.

Abiraterone acetate efficacy against prostate cancer is dependent on the circulating levels of abiraterone and its active metabolites, which present significant pharmacokinetic variability among patients. Thus, therapeutic drug monitoring can be performed to improve treatment outcomes. To support such studies, there are only a limited number of bioanalytical methods in current literature. This work presents a fast method to quantify abiraterone and D4A in plasma in 4 min by UPLC-MS/MS. Bioanalytical method validation was performed according to the recommendations of the US Food and Drug Administration. The method was linear within the range of 1-400 ng/ml for abiraterone and 0.2-20 ng/ml for D4A (r2 > 0.99). Based on the analysis of quality control samples at the lower limit of quantification, low, medium and high concentrations, the method was precise (CVabiraterone ≤ 9.72%; CVD4A ≤ 14.64%) and accurate (CVabiraterone 95.51-107.59%; CVD4A 98.04-99.89%). Application of the method to the quantification of abiraterone and D4A in 10 clinical samples revealed important variability in the conversion ratio of abiraterone to D4A (CV 90.85%). Considering the current literature, this is the fastest method to quantify abiraterone and D4A in plasma, allowing for optimization of the analytical routine.

Inter- and intra-patient variability in pharmacokinetics of abiraterone acetate in metastatic prostate cancer.

PURPOSE: This study examined the inter- and intra-patient variability in pharmacokinetics of AA and its metabolites abiraterone and Δ(4)-abiraterone (D4A), and potential contributing factors. METHODS: AA administered daily for ≥4 weeks concurrently with androgen deprivation therapy (ADT) for mCRPC were included. Pharmacokinetic evaluation was performed at two consecutive visits at least 4 weeks apart. Plasma samples were collected 24 h after last dose of AA to obtain drug trough level (DTL) of two active metabolites, abiraterone and D4A. RESULTS: 39 plasma samples were obtained from 22 patients, with 17 patients had repeat DTL measurement. Considerable inter-patient variability in DTL was seen, with initial DTL for abiraterone ranging between 1.5 and 25.4 ng/ml (CV 61%) and for D4A between 0.2 and 2.5 ng/ml (CV 61%). Intra-patient variability in DTL for abiraterone varied between 0.85 and 336% and for D4A between 1.14 and 199%. There was no increase in AA exposure with use of dexamethasone (n = 5; DTL 13.9) compared with prednisone (n = 17; DTL 11.0 p = 0.5), dosing in fasted state (n = 13, DTL 12.1) compared to dosing in fed state (n = 9; DTL 11.1, p = 0.8), or chemotherapy-exposed (n = 10; DTL 8.9) compared to chemotherapy naïve (n = 12; DTL 14.0, p = 0.1). CONCLUSIONS: Our cohort demonstrated high inter- and intra-patient variability in both abiraterone and D4A with fixed dosing of AA, with no effect from choice of corticosteroids, prior use of chemotherapy, or dosing in fasting state. Monitoring DTL of AA may be necessary to minimise risk of patients being under-dosed and earlier development of resistance.

Development of novel PLGA nanoparticles with co-encapsulation of docetaxel and abiraterone acetate for a highly efficient delivery into tumor cells.

Co-encapsulation of abiraterone acetate (AbrA) and docetaxel (Dtx) in polymeric nanoparticles as novel prototypes for prostate cancer treatment combining hormonal and chemotherapy was designed. Nanoparticles (NPs) composed of poly(dl-lactide-co-glycolide) (PLGA) were prepared by single-emulsion solvent evaporation technique and characterized in terms of morphology with atomic force microscopy and transmission electron microscopy. HPLC method for simultaneous determination of AbrA and Dtx encapsulation efficacy was developed. Also differential scanning calorimetry and Fourier-transform infrared spectroscopy were provided. To study the effectiveness of cellular internalization and distribution of NPs with AbrA and Dtx co-encapsulation (NP-AbrA/Dtx), a fluorescence microscopy was utilized. NPs prepared had size 256.3 ±9.4 nm and zeta potential -18.4 ±1.4 mV. Encapsulation efficacy for AbrA was 68.7% and for Dtx was 74.3%. NPs were able to control the AbrA and Dtx release within 24 h. The mathematical model of drug release was performed. The results obtained from confocal microscopy showed the effective accumulation of the NP-AbrA/Dtx in the cytoplasm of cells. Synthesized NPs possessed satisfactory parameters and a biphasic release profile, proceeding by the Fick diffusion mechanism, which provide prolonged release of the drugs and maintenance of their concentration. It was shown that NPs loaded with AbrA and Dtx exhibited a high cytotoxic activity on the LNCaP cell line, similar to the combination of free drugs of AbrA and Dtx, but in contrast to the combination of substances, had a synergistic mechanism of action. Our findings support the potential use of developed NPs in further in vivo studies. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 1150-1158, 2019.

Confirmation of the drug-drug interaction potential between cobicistat-boosted antiretroviral regimens and hormonal contraceptives.

BACKGROUND: Cobicistat (COBI), a CYP3A inhibitor, is a pharmacokinetic enhancer that increases exposures of the HIV protease inhibitors (PIs) atazanavir (ATV) and darunavir (DRV). The potential drug interaction between COBI-boosted PIs and hormonal contraceptives, which are substrates of intestinal efflux transporters and extensively metabolized by CYP enzymes, glucuronidation and sulfation, was evaluated. METHODS: This was a Phase I, open-label, two cohort (n=18/cohort), fixed-sequence study in healthy females that evaluated the drug-drug interaction (DDI) between multiple-dose ATV+COBI or DRV+COBI and single-dose drospirenone/ethinyl estradiol (EE). DDIs were evaluated using 90% confidence intervals of the geometric least-squares mean ratios of the test (drospirenone/EE+boosted PI) versus reference (drospirenone/EE) using lack of DDI boundaries of 70-143%. Safety was assessed throughout the study. RESULTS: 29/36 participants completed the study. Relative to drospirenone/EE alone, drospirenone area under the plasma concentration versus time curve extrapolated to infinity (AUCinf) was 1.6-fold and 2.3-fold higher, and maximum observed plasma concentration (Cmax) was unaltered, upon coadministration with DRV+COBI and ATV+COBI, respectively. EE AUCinf decreased 30% with drospirenone/EE + DRV+COBI and was unchanged with ATV+COBI + drospirenone/EE, relative to drospirenone/EE alone. Study treatments were generally well tolerated. The majority of adverse events were mild and consistent with known safety profiles of the compounds. CONCLUSIONS: Consistent with COBI-mediated CYP3A inhibition, drospirenone exposure increased following coadministration with COBI-containing regimens, with a greater increase with ATV+COBI. Thus, clinical monitoring for drospirenone-associated hyperkalaemia is recommended with DRV+COBI and ATV+COBI should not be used with drospirenone. Lower EE exposure with DRV+COBI may be attributed to inductive effects of DRV on CYP enzymes and/or intestinal efflux transporters (that is, P-gp) involved in EE disposition.

HSD3B1(1245A>C) variant regulates dueling abiraterone metabolite effects in prostate cancer.

BACKGROUND: A common germline variant in HSD3B1(1245A>C) encodes for a hyperactive 3ß-hydroxysteroid dehydrogenase 1 (3ßHSD1) missense that increases metabolic flux from extragonadal precursor steroids to DHT synthesis in prostate cancer. Enabling of extragonadal DHT synthesis by HSD3B1(1245C) predicts for more rapid clinical resistance to castration and sensitivity to extragonadal androgen synthesis inhibition. HSD3B1(1245C) thus appears to define a subgroup of patients who benefit from blocking extragonadal androgens. However, abiraterone, which is administered to block extragonadal androgens, is a steroidal drug that is metabolized by 3ßHSD1 to multiple steroidal metabolites, including 3-keto-5α-abiraterone, which stimulates the androgen receptor. Our objective was to determine if HSD3B1(1245C) inheritance is associated with increased 3-keto-5α-abiraterone synthesis in patients. METHODS: First, we characterized the pharmacokinetics of 7 steroidal abiraterone metabolites in 15 healthy volunteers. Second, we determined the association between serum 3-keto-5α-abiraterone levels and HSD3B1 genotype in 30 patients treated with abiraterone acetate (AA) after correcting for the determined pharmacokinetics. RESULTS: Patients who inherit 0, 1, and 2 copies of HSD3B1(1245C) have a stepwise increase in normalized 3-keto-5α-abiraterone (0.04 ng/ml, 2.60 ng/ml, and 2.70 ng/ml, respectively; P = 0.002). CONCLUSION: Increased generation of 3-keto-5α-abiraterone in patients with HSD3B1(1245C) might partially negate abiraterone benefits in these patients who are otherwise more likely to benefit from CYP17A1 inhibition. FUNDING: Prostate Cancer Foundation Challenge Award, National Cancer Institute.

Prospective International Randomized Phase II Study of Low-Dose Abiraterone With Food Versus Standard Dose Abiraterone In Castration-Resistant Prostate Cancer.

Purpose Abiraterone acetate (AA) is a standard of care for metastatic castration-resistant prostate cancer (CRPC). Despite a large food effect, AA was administered under fasting conditions in its pivotal trials. We sought to test the hypothesis that low-dose AA (LOW; 250 mg with a low-fat meal) would have comparable activity to standard AA (STD; 1,000 mg fasting) in patients with CRPC. Patients and Methods Patients (n = 72) with progressive CRPC from seven institutions in the United States and Singapore were randomly assigned to STD or LOW. Both arms received prednisone 5 mg twice daily. Prostate-specific antigen (PSA) was assessed monthly, and testosterone/dehydroepiandrosterone sulfate were assessed every 12 weeks with disease burden radiographic assessments. Plasma was collected for drug concentrations. Log change in PSA, as a pharmacodynamic biomarker for efficacy, was the primary end point, using a noninferiority design. Progression-free survival (PFS), PSA response (≥ 50% reduction), change in androgen levels, and pharmacokinetics were secondary end points. Results Thirty-six patients were accrued to both arms. At 12 weeks, there was a greater effect on PSA in the LOW arm (mean log change, -1.59) compared with STD (-1.19), and noninferiority of LOW was established according to predefined criteria. The PSA response rate was 58% in LOW and 50% in STD, and the median PFS was approximately 9 months in both groups. Androgen levels decreased similarly in both arms. Although there was no difference in PSA response or PFS, abiraterone concentrations were higher in STD. Conclusion Low-dose AA (with low-fat breakfast) is noninferior to standard dosing with respect to PSA metrics. Given the pharmacoeconomic implications, these data warrant consideration by prescribers, payers, and patients. Additional studies are indicated to assess the long-term efficacy of this approach.

Quantitation of the anticancer drug abiraterone and its metabolite Δ(4)-abiraterone in human plasma using high-resolution mass spectrometry.

Abiraterone acetate is administered as a prodrug to patients with metastatic, castration-resistant prostate cancer (mCRPC) and is readily metabolized into the potent 17a-hydroxylase/17,20-lyase (CYP17) enzyme inhibitor and androgen receptor inhibitor abiraterone and Δ(4)-abiraterone (D4A), respectively. To investigate pharmacokinetic variability in abiraterone acetate metabolism we developed highly sensitive liquid chromatography/mass spectrometry (LC/MS) assays for the simultaneous quantitation of abiraterone and D4A in human plasma using high-resolution mass spectrometry (HRMS) on an Orbitrap mass spectrometer. This study demonstrates the quantitative performance of HRMS and compares the conventional Parallel Reaction Monitoring (PRM) mode of quantitation with the unconventional Full scan MS mode conducted at high resolution (>70,000 resolution). The use of HRMS for quantitation of abiraterone and D4A yielded assays that were linear over a broad concentration range (0.074-509.6 ng/mL for abiraterone; 0.075-59.93 ng/mL for D4A) in both Full scan MS and PRM modes. The assay precision for abiraterone and D4A was below 5% in PRM mode and 7% in Full scan MS mode. Accuracies fell within 98-107% for abiraterone and 104-112% for D4A in PRM mode, and 96-116% for abiraterone and 96-105% for D4A in Full scan MS mode, each meeting the acceptance criteria of FDA approved guidelines for bioanalytical methods The PRM analysis of abiraterone and D4A provided high specificity and reduced background interference, however the Full scan MS detection at a resolution of 70,000 was advantageous in that it required minimal optimization, was simple to implement, yielded comparable quantitative characteristics to PRM and the data is useful for re-analysis. Use of the assays were demonstrated for quantitation of these metabolites in steady state trough level plasma of seventeen (17) patients with mCRPC, demonstrating the inter-patient variability of up to 10-fold concentration.

Phase I/II trial of cabazitaxel plus abiraterone in patients with metastatic castration-resistant prostate cancer (mCRPC) progressing after docetaxel and abiraterone.

Background: Abiraterone and cabazitaxel improve survival in patients with metastatic castration-resistant prostate cancer (mCRPC). We conducted an open-label phase I/II trial of cabazitaxel plus abiraterone to assess the antitumor activity and tolerability in patients with progressive mCRPC after docetaxel (phase I), and after docetaxel and abiraterone (phase II) (NCT01511536). Patients and methods: The primary objectives were to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of cabazitaxel plus abiraterone (phase I), and the prostate-specific antigen (PSA) response defined as a ≥ 50% decrease confirmed ≥3 weeks later with this combination (phase II). Results: Ten patients were enrolled in the phase I component; nine were evaluable. No DLTs were identified. The MTD was established as the approved doses for both drugs (cabazitaxel 25 mg/m2 every 3 weeks and abiraterone 1000 mg once daily). Daily abiraterone treatment did not impact on cabazitaxel clearance. Twenty-seven patients received cabazitaxel plus abiraterone plus prednisone (5 mg twice daily) in phase II. The median number of cycles administered (cabazitaxel) was seven (range: 1-28). Grade 3-4 treatment-emergent adverse events included asthenia (in 5 patients; 14%), neutropenia (in 5 patients; 14%) and diarrhea (in 3 patients; 8%). Nine patients (24%) required dose reductions of cabazitaxel. Of 26 evaluable patients, 12 achieved a PSA response [46%; 95% confidence interval (CI): 26.6-66.6%]. Median PSA-progression-free survival was 6.9 months (95% CI: 4.1-10.3 months). Of 14 patients with measurable disease at baseline, 3 (21%) achieved a partial response per response evaluation criteria in solid tumors. Conclusions: The combination of cabazitaxel and abiraterone has a manageable safety profile and shows antitumor activity in patients previously treated with docetaxel and abiraterone.

Relation between plasma trough concentration of abiraterone and prostate-specific antigen response in metastatic castration-resistant prostate cancer patients.

BACKGROUND: Abiraterone (ABI) is a major oral agent for the treatment of metastatic castration-resistant prostate cancer (mCRPC) patients but its systemic exposure is subject to a large inter-individual variability. We aimed to explore the relationship between ABI trough plasma concentration and prostate-specific antigen (PSA) response in mCRPC patients and to identify the critical determinants for its activity. PATIENTS AND METHODS: This is a monocentric prospective observational study in mCRPC patients treated with ABI. The plasmatic concentration of ABI at steady state was measured using liquid chromatography with fluorescence detection. The primary objective was to study the relationship between mean ABI plasma exposure (ABI Cmin) and 3-month PSA response. RESULTS: From 2012 to 2016, 61 mCRPC patients were eligible for pharmacokinetic/pharmacodynamic assessment. Thirty-eight patients experienced PSA response (62%, [confidence interval {CI} 95% 50-78]). In univariate analysis, ABI Cmin was 1.5-fold higher in responders: 12.0 ng/mL (CI 95% 9.4-15.6) versus 8.0 ng/mL (CI 95% 5.8-11.6; P = 0.0015). In multivariate analysis, only ABI Cmin was independently associated with PSA response (odds ratio = 1.12 [CI 95% 1.01-1.25], P = 0.004). By receiver operating characteristic analysis, the optimal threshold for ABI Cmin was 8.4 ng/mL. Progression-free survival (PFS) was significantly higher in patients with ABI Cmin above 8.4 ng/mL (hazard ratio 0.55, [CI 95% 0.31-0.99], 12.2 [CI 95% 9.2-19.5] versus 7.4 [CI 95% 5.5-14.7] months otherwise, P = 0.044). CONCLUSIONS: We showed that ABI trough concentration correlates with PSA response and PFS. Moreover, we could determine a cut-off value of plasmatic concentration for PSA response. Altogether, ABI concentration monitoring appears as a new approach to improve clinical outcome in mCPRC patients.

Pharmacokinetic interaction between the CYP3A4 inhibitor ketoconazole and the hormone drospirenone in combination with ethinylestradiol or estradiol.

AIMS: The present study was conducted to investigate the influence of the strong CYP3A4 inhibitor ketoconazole (KTZ) on the pharmacokinetics of drospirenone (DRSP) administered in combination with ethinylestradiol (EE) or estradiol (E2). METHODS: This was a randomized, multicentre, open label, one way crossover, fixed sequence study with two parallel treatment arms. A group sequential design allowed terminating the study for futility after first study cohort. About 50 healthy young women were randomized 1 : 1 to 'DRSP/EE' or 'DRSP/E2'. Subjects in the 'DRSP/EE' group received DRSP 3 mg/EE 0.02 mg (YAZ®, Bayer) once daily for 21 to 28 days followed by DRSP 3 mg/EE 0.02 mg once daily plus KTZ 200 mg twice daily for 10 days. Subjects in the 'DRSP/E2' group received DRSP 3 mg/E2 1.5 mg (research combination) once daily for 21 to 28 days followed by DRSP 3 mg/E2 1.5 mg once daily plus KTZ 200 mg twice daily for 10 days. RESULTS: Oral co-administration of DRSP/EE or DRSP/E2 and KTZ resulted in an increase in DRSP exposure (AUC(0,24 h)) in both treatment groups: DRSP/EE group: 2.68-fold DRSP increase (90% CI 2.44, 2.95); DRSP/E2 group: 2.30-fold DRSP increase (90% CI 2.08, 2.54). EE and estrone (metabolite of E2) exposures were increased ~1.4-fold whereas E2 exposure was largely unaffected by KTZ co-administration. CONCLUSIONS: A moderate pharmacokinetic drug-drug interaction between DRSP and KTZ was demonstrated in this study. No relevant changes of medical concern were detected in the safety data collected in this study.

Pharmacokinetics of abiraterone in healthy Japanese men: dose-proportionality and effect of food timing.

PURPOSE: Abiraterone acetate (AA) was recently approved for castration-resistant prostate cancer in Japan. Two phase 1 studies were conducted to assess the pharmacokinetics of abiraterone after single-dose administration in Japanese healthy men and to evaluate the effects of food timing on abiraterone pharmacokinetics after single-dose administration of AA in Japanese and Caucasian healthy men. METHODS: In the dose-proportionality study, subjects (n = 30 Japanese) were randomly assigned to receive single doses of 250, 500, and 1,000 mg AA, and in the food-timing study, subjects (n = 22 Japanese and n = 23 Caucasian) randomly received single doses of 1,000 mg AA under fasted (overnight) and three different modified fasting conditions. RESULTS: Mean C(max) and AUC(∞) for abiraterone increased dose-dependently in Japanese healthy men; however, 90 % confidential interval (CI) was outside the predefined dose-proportionality criteria. Based on geometric mean ratios and 90 % CIs (versus overnight fasting condition), abiraterone exposure (AUC) increased significantly with dosing 1 h premeal, 2 h postmeal, or in between two meals 4 h apart by 57 %, 595 %, and 649 %, respectively. CONCLUSION: No clinically meaningful difference was observed in the pharmacokinetics of abiraterone between Caucasian and Japanese subjects.

Clinical trial simulation to evaluate population pharmacokinetics and food effect: capturing abiraterone and nilotinib exposures.

The objectives of this study were to determine (1) the accuracy with which individual patient level exposure can be determined and (2) whether a known food effect can be identified in a trial simulation of a typical population pharmacokinetic trial. Clinical trial simulations were undertaken using NONMEM VII to assess a typical oncology pharmacokinetic trial design. Nine virtual trials for each compound were performed for combinations of different levels of between-occasion variability, number of patients in the trial, and magnitude of a food covariate on oral clearance. Less than 5% and 20% bias and precision were obtained in individual clearance estimated for both abiraterone and nilotinib using this design. This design resulted in biased and imprecise population clearance estimates for abiraterone. The between-occasion variability in most trials was captured with less than 30% of percent bias and precision. The food effect was detectable as a statistically significant covariate on oral clearance for abiraterone and nilotinib with percent bias and precision of the food covariate less than 20%. These results demonstrate that clinical trial simulation can be used to explore the ability of specific trial designs to evaluate the power to identify individual and population level exposures, covariate, and variability effects.

Chemical synthesis, cytotoxicity, selectivity and bioavailability of 5α-androstane-3α,17ß-diol derivatives.

Aminosteroid derivatives represent a new family of compounds with promising antiproliferative activity over different cancer cell lines. Among all the aminosteroid derivatives synthesised in our laboratory, we have identified E-37P as one of the more potent when tested in vitro. Unfortunately, the pharmacokinetic properties of E-37P decrease its effectiveness when tested in vivo. To improve the bioavailability and increase the efficiency of aminosteroid E-37P, two series of analog compounds were synthesised by classic chemical synthesis, they were then characterized, and the concentration that inhibits 50% of cell proliferation (IC50) was determined on different cell lines. RM-133, a 5α-androstane-3α,17ß-diol derivative with a quinoline nucleus at the end of the piperazine-proline side-chain at position 2ß and an ethinyl at position 17α, showed very good antiproliferative activity among the five cancer cell lines studied (IC50=0.1, 0.1, 0.1, 2.0 and 1.1 µM for HL-60, MCF-7, T-47D, LNCaP and WEHI-3, respectively). Moreover, the plasmatic concentration of RM-133 at 3h, when injected subcutaneously in rats, was 2.3-fold higher than that of E-37P (151 vs 64.8 ng/mL). Furthermore, RM-133 weakly inhibited the two representative liver enzymes, CYP3A4 and CYP2D6, indicating a very low risk of drug-drug interactions. The cytotoxicity of RM-133 against normal cells was tested on peripheral blood lymphocytes (PBL) obtained from different donors and previously activated with phytohemagglutinin-L. PBL responded differently to treatment with RM-133, we observed a stimulation of cell proliferation and/or cytotoxicity in a dose-dependent manner. Based on these results, additional studies are currently underway to evaluate the selectivity of our lead compound against normal cell lines in a more detailed fashion.

Population pharmacokinetic analysis of abiraterone in chemotherapy-naïve and docetaxel-treated patients with metastatic castration-resistant prostate cancer.

BACKGROUND AND OBJECTIVES: Abiraterone acetate, an androgen biosynthesis inhibitor, prolongs survival in men with metastatic castration-resistant prostate cancer (mCRPC) in the pre- and post-chemotherapy setting as demonstrated by the pivotal phase III studies COU-AA-301 and COU-AA-302. We performed population pharmacokinetic analyses to estimate pharmacokinetic parameters after oral administration of 1,000 mg/day of abiraterone acetate in patients with mCRPC, with or without prior chemotherapy, and after a single 1,000 mg dose in healthy volunteers. The study objectives were to determine consistency between patient populations and to characterize factors that may influence abiraterone pharmacokinetics. METHODS: Studies in this analysis included COU-AA-302 (chemotherapy naïve); COU-AA-301 and COU-AA-006 (chemotherapy pretreated); and COU-AA-008, COU-AA-009, and COU-AA-014 (healthy subjects). A total of 4,627 plasma concentrations from 359 subjects (62 healthy volunteers, 297 patients) were analyzed using non-linear mixed-effects modeling. RESULTS: An Erlang-type absorption model with first-order elimination and three-transit compartments following sequential zero- and first-order processes was used to characterize abiraterone pharmacokinetics. Absorption-related parameters were affected by food intake. Abiraterone pharmacokinetics were characterized by an extensive apparent clearance, which was lower in patients with mCRPC (1,550 L/h) versus healthy subjects (2,240 L/h), and by large apparent central (5,620 L) and peripheral (17,400 L) volumes of distribution. Abiraterone pharmacokinetics were similar in chemotherapy-pretreated and -naïve patients and were characterized by a high between- and within-subject variability [e.g., between-subject coefficient of variation (CV%) for relative bioavailability for the modified fasting state was 61.1% and the CV% for within-subject variability was 71.3%]. The fat content of food taken with abiraterone acetate affected the bioavailability of abiraterone. No factors beyond food intake and health status (healthy vs. mCRPC) impacted abiraterone pharmacokinetics. CONCLUSIONS: Based on the pharmacokinetics model, the recommended 1,000 mg/day of abiraterone acetate resulted in similar abiraterone exposure for patients with mCRPC regardless of prior chemotherapy. The fat content of food affected relative bioavailability of abiraterone, though the extent of this effect is dependent on health status.

Population pharmacokinetic/pharmacodynamic evaluation of low-dose drospirenone with 17ß-estradiol in postmenopausal women with moderate to severe vasomotor symptoms.

OBJECTIVE: This study aims to characterize the pharmacokinetics/pharmacodynamics of drospirenone and estradiol in the treatment of postmenopausal women with moderate to severe vasomotor symptoms and to explore the relationship between the serum exposures of estradiol and drospirenone and efficacy, measured by reductions in moderate to severe hot flushes. METHODS: Participants in a 12-week, double-blind, randomized, placebo-controlled study of daily drospirenone/estradiol in two low-dose combinations (0.25 mg/0.5 mg and 0.5 mg/0.5 mg), estradiol (0.3 mg), or placebo provided infrequent serum samples for pharmacokinetic analysis of estradiol and drospirenone, with additional frequent sampling during 24 hours in a study subset. RESULTS: Estradiol steady-state serum concentrations were described by a one-compartmental model with first-order elimination and zero-order absorption. The pharmacokinetics of drospirenone was described by a linear open two-compartment model with first-order elimination kinetics from the central compartment and delayed first-order absorption kinetics. A total of 1,516 serum estradiol concentrations and 736 serum drospirenone concentrations (n = 251) from 383 women were evaluated. Baseline estradiol concentrations increased with rising body mass index, and apparent clearance of estradiol at steady state was 39% higher in smokers versus nonsmokers. The serum exposures of both estradiol and drospirenone affected efficacy, as analyzed by a generalized linear model. Smoking had a negative effect on the efficacy of hormone therapy. CONCLUSIONS: The efficacy of low-dose drospirenone/estradiol for reducing vasomotor symptoms correlates with the serum exposure of estradiol and, for the first time, the serum exposure of drospirenone. Smoking adversely affects the clearance of estradiol and the efficacy of treatment.

Bioequivalence evaluation of a folate-supplemented oral contraceptive containing ethinylestradiol/drospirenone/levomefolate calcium versus ethinylestradiol/drospirenone and levomefolate calcium alone.

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