Pharmacokinetic and pharmacodynamic comparison of subcutaneous versus intramuscular leuprolide acetate formulations in male subjects.

BACKGROUND: The aim of this study was to compare the pharmacokinetics (PK) and pharmacodynamics (PD) of two distinct formulations of leuprolide acetate (LA); subcutaneous (SC) injection and intramuscular (IM) injection. METHODS: A total of 32 healthy men were randomized to receive a single 7.5 mg injection of SC-LA (n = 16) or IM-LA (n = 16) in this phase I, open-label, parallel-group study. PK was assessed via LA concentrations, and PD via serum luteinizing hormone (LH) and testosterone (T) concentrations. RESULTS: The initial surge of LA was higher for IM-LA than SC-LA (Cmax 27 ± 4.9 versus 19 ± 8.0 ng/ml, respectively), with a shorter tmax (1.0 ± 0.4 versus 2.1 ± 0.8 h). The duration of quantifiable LA concentration was longer for SC-LA (up to 56 versus 42 days for SC-LA and IM-LA, respectively). Median LH concentrations in both groups rapidly increased, followed by gradual decrease. However, SC-LA demonstrated a longer duration of LH suppression, with median levels remaining below 1.0 IU/l through Day 56 compared with IM-LA where LH started to rise by Day 35. Consequently, serum T began to increase by Day 42 in the IM-LA group, with only four subjects maintaining levels ⩽50 ng/dl, compared with 14 subjects in the SC-LA group. By Day 56, 13 SC-LA subjects maintained serum T levels ⩽50 ng/dl. Both SC-LA and IM-LA were well tolerated. CONCLUSIONS: Both formulations demonstrated consistent delivery of drug over 1 month; however, SC-LA provided a longer duration of action than expected based on the dosing interval. This profile suggests that SC-LA will provide effective suppression of T over a longer period of time, permitting greater injection scheduling flexibility.

Polymer-delivered subcutaneous leuprolide acetate formulations achieve and maintain castrate concentrations of testosterone in four open-label studies in patients with advanced prostate cancer.

OBJECTIVE: To determine whether luteinising hormone-releasing hormone (LHRH) agonist, ATRIGEL® polymer-delivered, subcutaneous, leuprolide acetate (ADSC-LA), formulations suppressed serum testosterone to concentrations of ≤20 ng/dL. PATIENTS AND METHODS: Data from four open-label, fixed-dose studies were evaluated. Male patients aged 40-86 years with advanced prostatic adenocarcinoma, whom had not undergone prior androgen-deprivation therapy (ADT), were treated with a depot formulation of ADSC-LA: 7.5 mg (1-month, 120 patients), 22.5 mg (3-month, 117 patients), 30 mg (4-month, 90 patients), or 45 mg (6-month, 111 patients). Serum testosterone was sampled at screening, baseline, 2, 4, 8 h after dosing, 1, 2, 3, and 7 days, and every week until the next dose, at which time, the sampling schedule repeated until the end of study (24 weeks for 1- and 3-month formulations, 32 weeks for 4-month, and 48 weeks for the 6-month). The primary analyses were mean serum testosterone concentrations and proportion of patients who achieved concentrations of ≤20 ng/dL. RESULTS: The mean (SE) serum testosterone concentrations at the end of study were consistently ≤20 ng/dL in each study, at 6.1 (0.4), 10.1 (0.7), 12.4 (0.8), and 12.6 (2.1) ng/dL for the 1-, 3-, 4-, and 6-month formulations, respectively. A high proportion of patients (94%, 90%, 92%, 96% for the 1-, 3-, 4-, and 6-month formulations, respectively) achieved testosterone concentrations of ≤20 ng/dL within 6 weeks, and 90-97% of patients in all studies maintained concentrations of ≤20 ng/dL from weeks 6-24. CONCLUSIONS: Recent studies have shown improved outcomes in patients with prostate cancer who consistently attained a more rigorous level of testosterone suppression (≤20 ng/dL) with ADT than the historical standard (≤50 ng/dL). All doses of ADSC-LA rapidly achieved and maintained mean serum testosterone to the more rigorous target concentration of ≤20 ng/dL. These data suggest that ADSC-LA delivers equivalent testosterone suppression as achieved by surgical castration.

Effect of a single course of isotretinoin therapy on bone mineral density in adolescent patients with severe, recalcitrant, nodular acne.

BACKGROUND: Adverse changes in bone have been reported for patients undergoing high-dose, long-term (several years) isotretinoin therapy for disorders of cornification. The effect of short-term (4-5 months) therapy at the lower dose recommended for acne on bone development in younger, growing adolescent (12-17 years) patients has not been well studied. OBJECTIVE: The purpose of the study was to evaluate the effect of a standard, single course of isotretinoin (Accutane) therapy on bone mineral density (BMD) of the lumbar spine and hip in adolescents ages 12 to 17 years with severe, recalcitrant, nodular acne. METHODS: In this open-label, multicenter study, 217 adolescents (81 girls) with severe, recalcitrant, nodular acne were enrolled and treated with isotretinoin twice daily with food at the recommended total dose of approximately 1 mg/kg for 16 to 20 weeks. BMD in the lumbar spine and hip was measured at baseline and at the end of therapy by dual energy radiograph absorptiometry. RESULTS: There was no clinically significant mean change in BMD measured at the lumbar spine (+1.4%, range: -4.9% to +12.3%) or total hip (-0.26%, range: -11.3% to +15.0%). Hyperostosis was not observed in any patient. Typical efficacy expected in the treatment of acne was observed. CONCLUSIONS: A 16- to 20-week course of isotretinoin treatment at the recommended dose for severe acne has no clinically significant effect on lumbar spine and total hip BMD in the adolescent (12-17 years) population.

The effect of isotretinoin on the pharmacokinetics and pharmacodynamics of ethinyl estradiol and norethindrone.

BACKGROUND: Isotretinoin is a known teratogen, and when it is prescribed to women of childbearing potential, 2 forms of contraception must be used, commonly including hormonal contraception. Although isotretinoin and estradiol are metabolized largely by cytochrome P450 (CYP) 3A4 and glucuronidation, the potential for clinical drug interaction, with subsequent pharmacodynamic impact, has not been evaluated. METHODS: We enrolled 26 healthy women who were to receive isotretinoin for the treatment of severe, recalcitrant nodular acne and who were taking or planning to take oral contraceptives. The pharmacokinetics of ethinyl estradiol and norethindrone (INN, norethisterone) (the components of Ortho Novum 7/7/7; Ortho-McNeil Pharmaceutical, Inc, Raritan, NJ) and pharmacodynamic assessments of oral contraceptive effectiveness (concentrations of serum progesterone, luteinizing hormone, and follicle-stimulating hormone) were determined on days 6 and 20 of 2 separate oral contraceptive cycles, before and during isotretinoin treatment. RESULTS: The addition of isotretinoin to the oral contraceptive regimen resulted in small and inconsistent, although statistically significant (P <.04), decreases in the concentrations of both ethinyl estradiol (9% decrease in area under the plasma concentration-time curve from time 0 to 24 hours after the dose on day 6) and norethindrone (11% decrease in maximum plasma concentration on day 20). Isotretinoin did not cause any statistically significant increases in pharmacodynamic markers, although a majority of women had increases in these measures. Although there was no correlation between isotretinoin (or metabolite) levels and oral contraceptive levels (P >.05), there was a correlation between progesterone level and oral contraceptive levels (P <.05). Variability was large for both pharmacokinetic measures (median coefficients of variation of 44%-69% [for each time point within a study period]) and pharmacodynamic measures (median coefficients of variation of 64%-114%). One woman in each study phase, one before and one during isotretinoin treatment, had a progesterone elevation consistent with possible ovulation. No serious or unexpected adverse events were observed. CONCLUSIONS: The small reduction in ethinyl estradiol and norethindrone levels associated with isotretinoin was not associated with any pharmacodynamic changes in our study. The combination of the teratogenic risk of isotretinoin and the large variability of and correlation between oral contraceptive levels and pharmacodynamic measures, however, strongly reinforces the necessity of additional contraceptive methods during concomitant administration of these drugs.