James Jiao

Abiraterone Acetate to Lower Androgens in Women With Classic 21-Hydroxylase Deficiency

CONTEXT Chronic supraphysiological glucocorticoid therapy controls the androgen excess of 21-hydroxylase deficiency (21OHD) but contributes to the high prevalence of obesity, glucose intolerance, and reduced bone mass in these patients. Abiraterone acetate (AA) is a prodrug for abiraterone, a potent CYP17A1 inhibitor used to suppress androgens in the treatment of prostate cancer. OBJECTIVE The objective of the study was to test the hypothesis that AA added to physiological hydrocortisone and 9α-fludrocortisone acetate corrects androgen excess in women with 21OHD without causing hypertension or hypokalemia. DESIGN This was a phase 1 dose-escalation study. SETTING The study was conducted at university clinical research centers. PARTICIPANTS We screened 14 women with classic 21OHD taking hydrocortisone 12.5-20 mg/d to enroll six participants with serum androstenedione greater than 345 ng/dL (>12 nmol/L). INTERVENTION AA was administered for 6 days at 100 or 250 mg every morning with 20 mg/d hydrocortisone and 9α-fludrocortisone acetate. MAIN OUTCOME MEASURE The primary endpoint was normalization of mean predose androstenedione on days 6 and 7 (< 230 ng/dL [<8 nmol/L)] in greater than 80% of participants. Secondary end points included serum 17-hydroxyprogesterone and testosterone (T), electrolytes, plasma renin activity, and urine androsterone and etiocholanolone glucuronides. RESULTS With 100 mg/d AA, mean predose androstenedione fell from 764 to 254 ng/dL (26.7-8.9 nmol/L). At 250 mg/d AA, mean androstenedione normalized in five participants (83%) and decreased from 664 to 126 ng/dL (23.2-4.4 nmol/L), meeting the primary end point. Mean androstenedione declined further during day 6 to 66 and 38 ng/dL (2.3 and 1.3 nmol/L) at 100 and 250 mg/d, respectively. Serum T and urinary metabolites declined similarly. Abiraterone exposure was strongly negatively correlated with mean androstenedione. Hypertension and hypokalemia were not observed. CONCLUSION AA 100-250 mg/d added to replacement hydrocortisone normalized several measures of androgen excess in women with classic 21OHD and elevated serum androstenedione.

Food effects on abiraterone pharmacokinetics in healthy subjects and patients with metastatic castration‐resistant prostate cancer

Food effect on abiraterone pharmacokinetics and safety on abiraterone acetate coadministration with low‐fat or high‐fat meals was examined in healthy subjects and metastatic castration‐resistant prostate cancer (mCRPC) patients. Healthy subjects (n = 36) were randomized to abiraterone acetate (single dose, 1000 mg) + low‐fat meal, + high‐fat meal, and fasted state. mCRPC patients received repeated doses (abiraterone acetate 1000 mg + 5 mg prednisone twice daily; days 1–7) in a modified fasting state followed by abiraterone acetate plus prednisone within 0.5 hours post–low‐fat (n = 6) or high‐fat meal (n = 18; days 8–14). In healthy subjects, geometric mean (GM) abiraterone area under plasma concentration–time curve (AUC) increased ∼5‐ and ∼10‐fold, respectively, with low‐fat and high‐fat meals versus fasted state (GM [coefficient of variation], 1942 [48] and 4077 [37] ng · h/mL vs 421 [67] ng · h/mL, respectively). In mCRPC patients, abiraterone AUC was ∼2‐fold higher with a high‐fat meal and similar with a low‐fat meal versus modified fasting state (GM [coefficient of variation]: 1992 [34] vs 973 [58] ng · h/mL and 1264 [65] vs 1185 [90] ng · h/mL, respectively). Adverse events (all grade ≤ 3) were similar, with high‐fat/low‐fat meals or fasted/modified fasting state. Short‐term dosing with food did not alter abiraterone acetate safety.

Impact on abiraterone pharmacokinetics and safety: Open-label drug–drug interaction studies with ketoconazole and rifampicin

We evaluated the impact of a strong CYP3A4 inhibitor, ketoconazole, and a strong inducer, rifampicin, on the pharmacokinetic (PK) exposure of abiraterone in two studies in healthy men. All subjects received 1,000 mg of abiraterone acetate on Days 1 and 14. Study A subjects (n = 20) received 400 mg ketoconazole on Days 11–16. Study B subjects (n = 19) received 600 mg rifampicin on Days 8–13. Serial PK sampling was done on Days 1 and 14. Study A: When given with ketoconazole, abiraterone exposure increased by 9% for maximum plasma concentration (Cmax) and 15% for area under the plasma concentration–time curve from 0 to time of the last quantifiable concentration (AUClast) and AUC from time 0 to infinity (AUC∞) compared to abiraterone acetate alone. Study B: When given with rifampicin, abiraterone exposure was reduced to 45% for Cmax and AUC∞ and to 42% for AUClast compared to abiraterone acetate alone. Ketoconazole had no clinically meaningful impact on abiraterone exposure. Rifampicin decreased abiraterone exposure by half. Hence, strong CYP3A4 inducers should be avoided or used with careful evaluation of clinical efficacy when administered with abiraterone acetate.

Single‐dose pharmacokinetic studies of abiraterone acetate in men with hepatic or renal impairment

Three open‐label, single‐dose studies investigated the impact of hepatic or renal impairment on abiraterone acetate pharmacokinetics and safety/tolerability in non‐cancer patients. Patients (n = 8 each group) with mild/moderate hepatic impairment or end‐stage renal disease (ESRD), and age‐, BMI‐matched healthy controls received a single oral 1,000 mg abiraterone acetate (tablet dose); while patients (n = 8 each) with severe hepatic impairment and matched healthy controls received 125‐ and 2,000‐mg abiraterone acetate (suspension doses), respectively (systemic exposure of abiraterone acetate suspension is approximately half to that of tablet formulation). Blood was sampled at specified timepoints up to 72 or 96 hours postdose to measure plasma abiraterone concentrations. Abiraterone exposure was comparable between healthy controls and patients with mild hepatic impairment or ESRD, but increased by 4‐fold in patients with moderate hepatic impairment. Despite a 16‐fold reduction in dose, abiraterone exposure in patients with severe hepatic impairment was about 22% and 44% of the Cmax and AUC∞ of healthy controls, respectively. These results suggest that abiraterone pharmacokinetics were not changed markedly in patients with ESRD or mild hepatic impairment. However, the capacity to eliminate abiraterone was substantially compromised in patients with moderate or severe hepatic impairment. A single‐dose administration of abiraterone acetate was well‐tolerated.

In Vitro and In Vivo Drug-Drug Interaction Studies to Assess the Effect of Abiraterone Acetate, Abiraterone, and Metabolites of Abiraterone on CYP2C8 Activity

Abiraterone acetate, the prodrug of the cytochrome P450 C17 inhibitor abiraterone, plus prednisone is approved for treatment of metastatic castration-resistant prostate cancer. We explored whether abiraterone interacts with drugs metabolized by CYP2C8, an enzyme responsible for the metabolism of many drugs. Abiraterone acetate and abiraterone and its major metabolites, abiraterone sulfate and abiraterone sulfate N-oxide, inhibited CYP2C8 in human liver microsomes, with IC50 values near or below the peak total concentrations observed in patients with metastatic castration-resistant prostate cancer (IC50 values: 1.3–3.0 µM, 1.6–2.9 µM, 0.044–0.15 µM, and 5.4–5.9 µM, respectively). CYP2C8 inhibition was reversible and time-independent. To explore the clinical relevance of the in vitro data, an open-label, single-center study was conducted comprising 16 healthy male subjects who received a single 15-mg dose of the CYP2C8 substrate pioglitazone on day 1 and again 1 hour after the administration of abiraterone acetate 1000 mg on day 8. Plasma concentrations of pioglitazone, its active M-III (keto derivative) and M-IV (hydroxyl derivative) metabolites, and abiraterone were determined for up to 72 hours after each dose. Abiraterone acetate increased exposure to pioglitazone; the geometric mean ratio (day 8/day 1) was 125 [90% confidence interval (CI), 99.9–156] for Cmax and 146 (90% CI, 126–171) for AUClast. Exposure to M-III and M-IV was reduced by 10% to 13%. Plasma abiraterone concentrations were consistent with previous studies. These results show that abiraterone only weakly inhibits CYP2C8 in vivo.

Single-dose pharmacokinetics of ibrutinib in subjects with varying degrees of hepatic impairment*

Abstract This open-label, single-dose study was designed to characterize pharmacokinetics and safety profile of ibrutinib in hepatically impaired subjects. Each subject received single oral dose of ibrutinib (140 mg) following an overnight fast (hepatic impairment-mild [n = 6], moderate [n = 10], and severe [n = 8]; healthy control [n = 6]). Subjects with hepatic impairment showed significant increase in ibrutinib plasma exposures and fraction unbound ibrutinib. Compared to control group, mean exposure (AUClast; unbound) in mild, moderate, and severe cohorts was 4.1-, 9.8-, 13.4-fold higher, respectively. Terminal half-life trended slightly longer in moderately and severely impaired subjects, but risk of accumulation on repeated dosing appears negligible as half-life did not exceed 10 h. Based on observed effects on exposure, reduced doses are recommended for patients with mild and moderate liver impairment (Child–Pugh Class A and B), whereas 140 mg is considered too high for severely impaired patients (Class-C). A single dose of 140 mg was well tolerated in this study (NCT01767948).

A drug–drug interaction study of ibrutinib with moderate/strong CYP3A inhibitors in patients with B-cell malignancies

Abstract This was an open-label, multicenter, phase-1 study to evaluate the drug interaction between steady-state ibrutinib and moderate (erythromycin) and strong (voriconazole) CYP3A inhibitors in patients with B-cell malignancies and to confirm dosing recommendations. During cycle 1, patients received oral ibrutinib 560 mg qd alone (Days 1–4 and 14–18), and ibrutinib 140 mg (Days 5–13; 19–27) plus erythromycin 500 mg tid (Days 5–11) and voriconazole 200 mg bid (Days 19–25). Twenty-six patients (median [range] age: 64.5 [50–88] years) were enrolled. Geometric mean ratio (90% confidence intervals) after co-administration of ibrutinib 140 mg with erythromycin and voriconazole was 74.7 (53.97–103.51) and 143.3 (107.77–190.42), respectively, versus ibrutinib 560 mg alone. The most common (≥20%) adverse events were diarrhea (27%) and neutropenia (23%). The results demonstrate that ibrutinib 140 mg with voriconazole or erythromycin provides exposure within the clinical range for patients with B-cell malignancies.

Correction to: Ibrutinib does not prolong the corrected QT interval in healthy subjects: results from a thorough QT study

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