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Open-label, phase I, pharmacokinetic studies of abiraterone acetate in healthy men.

Acharya M, Bernard A, Gonzalez M, Jiao J, De Vries R, Tran N - Cancer Chemother. Pharmacol. (2012)

Bottom Line: To evaluate pharmacokinetics, safety, and tolerability of abiraterone acetate (AA) in healthy men.Single doses of AA were well tolerated in healthy men, and safety profile was consistent with its known toxicities in CRPC patients.Systemic exposure to abiraterone increased with increasing doses of AA (250-1,000 mg) in healthy men; AA was well tolerated in this population.

View Article: PubMed Central - PubMed

Affiliation: Janssen Research and Development, LLC, 920 Route 202 South, Raritan, NJ 08869, USA. macharya@its.jnj.com

ABSTRACT

Purpose: To evaluate pharmacokinetics, safety, and tolerability of abiraterone acetate (AA) in healthy men.

Methods: Two phase I studies (dose-escalation study and dose-proportionality study) were conducted in healthy men aged 18-55 years. All subjects received 4 consecutive single doses of AA (250, 500, 750 and 1,000 mg). The dose-escalation study subjects (N = 33) received AA doses in a sequential manner, starting with the lowest dose. The dose-proportionality study subjects (N = 32) were randomly allocated (1:1:1:1) to receive each of the 4 doses in a four-way crossover design.

Results: A dose-related increase in abiraterone exposure was observed in both studies. Over the evaluated dose range, the mean abiraterone maximum plasma concentrations increased from 26 to 112 ng/mL in dose-escalation study and from 40 to 125 ng/mL in dose-proportionality study; the mean area under the plasma concentration-time curve from 0 to the last measurable plasma concentration increased from 155 to 610 ng.h/mL in dose-escalation study, and from 195 to 607 ng.h/mL in dose-proportionality study. In the dose-proportionality study, abiraterone exposure was dose proportional between 1,000 and 750 mg doses; however, the exposure was slightly greater than dose proportional when exposures at 500 and 250 mg doses were compared with the exposure at 1,000 mg. Single doses of AA were well tolerated in healthy men, and safety profile was consistent with its known toxicities in CRPC patients.

Conclusion: Systemic exposure to abiraterone increased with increasing doses of AA (250-1,000 mg) in healthy men; AA was well tolerated in this population.

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Related in: MedlinePlus

a Mean (SD) serum testosterone levels over time in dose-escalation study. b Mean (SD) serum luteinizing hormone levels over time in dose-escalation study. c Mean (SD) serum testosterone levels over time in dose-proportionality study. d Mean (SD) serum luteinizing hormone levels over time in dose-proportionality study. n = 8 for all treatment groups except for 500 mg abiraterone acetate group (n = 9)
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Fig2: a Mean (SD) serum testosterone levels over time in dose-escalation study. b Mean (SD) serum luteinizing hormone levels over time in dose-escalation study. c Mean (SD) serum testosterone levels over time in dose-proportionality study. d Mean (SD) serum luteinizing hormone levels over time in dose-proportionality study. n = 8 for all treatment groups except for 500 mg abiraterone acetate group (n = 9)

Mentions: In the dose-escalation study, mean serum total testosterone values were generally lowest on day 3 (the first postdose timepoint at which the testosterone levels were measured in the dose-escalation study) and approached the baseline values by day 5 (Fig. 2a), and mean serum LH values were highest on day 3 and approached the baseline values by day 8 (Fig. 2b). In the dose-proportionality study, oral administration of AA 250–1,000 mg/day resulted in transient decrease in the mean serum testosterone levels. The maximum decrease was observed at 12 h postdose (the first postdose timepoint at which the testosterone levels were measured in the dose-proportionality study), with mean values returning to baseline by 72 h for the 250 and 500 mg doses and by 144 h for the 750 and 1,000 mg doses (Fig. 2c). Administration of AA also resulted in increase in mean serum LH levels, with maximum increase observed at 12 h postdose (Fig. 2d).Fig. 2


Open-label, phase I, pharmacokinetic studies of abiraterone acetate in healthy men.

Acharya M, Bernard A, Gonzalez M, Jiao J, De Vries R, Tran N - Cancer Chemother. Pharmacol. (2012)

a Mean (SD) serum testosterone levels over time in dose-escalation study. b Mean (SD) serum luteinizing hormone levels over time in dose-escalation study. c Mean (SD) serum testosterone levels over time in dose-proportionality study. d Mean (SD) serum luteinizing hormone levels over time in dose-proportionality study. n = 8 for all treatment groups except for 500 mg abiraterone acetate group (n = 9)
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3362727&req=5

Fig2: a Mean (SD) serum testosterone levels over time in dose-escalation study. b Mean (SD) serum luteinizing hormone levels over time in dose-escalation study. c Mean (SD) serum testosterone levels over time in dose-proportionality study. d Mean (SD) serum luteinizing hormone levels over time in dose-proportionality study. n = 8 for all treatment groups except for 500 mg abiraterone acetate group (n = 9)
Mentions: In the dose-escalation study, mean serum total testosterone values were generally lowest on day 3 (the first postdose timepoint at which the testosterone levels were measured in the dose-escalation study) and approached the baseline values by day 5 (Fig. 2a), and mean serum LH values were highest on day 3 and approached the baseline values by day 8 (Fig. 2b). In the dose-proportionality study, oral administration of AA 250–1,000 mg/day resulted in transient decrease in the mean serum testosterone levels. The maximum decrease was observed at 12 h postdose (the first postdose timepoint at which the testosterone levels were measured in the dose-proportionality study), with mean values returning to baseline by 72 h for the 250 and 500 mg doses and by 144 h for the 750 and 1,000 mg doses (Fig. 2c). Administration of AA also resulted in increase in mean serum LH levels, with maximum increase observed at 12 h postdose (Fig. 2d).Fig. 2

Bottom Line: To evaluate pharmacokinetics, safety, and tolerability of abiraterone acetate (AA) in healthy men.Single doses of AA were well tolerated in healthy men, and safety profile was consistent with its known toxicities in CRPC patients.Systemic exposure to abiraterone increased with increasing doses of AA (250-1,000 mg) in healthy men; AA was well tolerated in this population.

View Article: PubMed Central - PubMed

Affiliation: Janssen Research and Development, LLC, 920 Route 202 South, Raritan, NJ 08869, USA. macharya@its.jnj.com

ABSTRACT

Purpose: To evaluate pharmacokinetics, safety, and tolerability of abiraterone acetate (AA) in healthy men.

Methods: Two phase I studies (dose-escalation study and dose-proportionality study) were conducted in healthy men aged 18-55 years. All subjects received 4 consecutive single doses of AA (250, 500, 750 and 1,000 mg). The dose-escalation study subjects (N = 33) received AA doses in a sequential manner, starting with the lowest dose. The dose-proportionality study subjects (N = 32) were randomly allocated (1:1:1:1) to receive each of the 4 doses in a four-way crossover design.

Results: A dose-related increase in abiraterone exposure was observed in both studies. Over the evaluated dose range, the mean abiraterone maximum plasma concentrations increased from 26 to 112 ng/mL in dose-escalation study and from 40 to 125 ng/mL in dose-proportionality study; the mean area under the plasma concentration-time curve from 0 to the last measurable plasma concentration increased from 155 to 610 ng.h/mL in dose-escalation study, and from 195 to 607 ng.h/mL in dose-proportionality study. In the dose-proportionality study, abiraterone exposure was dose proportional between 1,000 and 750 mg doses; however, the exposure was slightly greater than dose proportional when exposures at 500 and 250 mg doses were compared with the exposure at 1,000 mg. Single doses of AA were well tolerated in healthy men, and safety profile was consistent with its known toxicities in CRPC patients.

Conclusion: Systemic exposure to abiraterone increased with increasing doses of AA (250-1,000 mg) in healthy men; AA was well tolerated in this population.

Show MeSH
Related in: MedlinePlus