FDA Approval Summary: Niraparib for the Maintenance Treatment of Patients with Recurrent Ovarian Cancer in Response to Platinum-Based Chemotherapy.

The FDA approved niraparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, on March 27, 2017, for maintenance treatment of patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response to platinum-based chemotherapy. Approval was based on data from the NOVA trial comparing niraparib with placebo in two independent cohorts, based on germline BRCA mutation status (gBRCAm vs. non-gBRCAm). Progression-free survival (PFS) in each cohort was the primary endpoint. In the gBRCAm cohort, estimated median PFS on niraparib was 21 months versus 5.5 months on placebo [HR, 0.26; 95% confidence interval (CI), 0.17-0.41; P < 0.0001]. In the non-gBRCAm cohort, estimated median PFS for niraparib and placebo was 9.3 and 3.9 months, respectively (HR, 0.45; 95% CI, 0.34-0.61; P < 0.0001). Common adverse reactions (>20% and higher incidence in the niraparib arm) with niraparib included thrombocytopenia, anemia, neutropenia, nausea, constipation, vomiting, mucositis, fatigue, decreased appetite, headache, insomnia, nasopharyngitis, dyspnea, rash, and hypertension. There were five cases of myelodysplastic syndrome and acute myeloid leukemia (1.4%) in patients treated with niraparib compared with two cases (1.1%) on placebo. Niraparib is the first PARP inhibitor approved as maintenance therapy for patients with ovarian, fallopian tube, or primary peritoneal cancer, with improvement in PFS, regardless of gBRCAm status. Clin Cancer Res; 24(17); 4066-71. ©2018 AACRSee related commentary by Konstantinopoulos and Matulonis, p. 4062.

Single- and multiple-dose bioequivalence of two once-daily tramadol formulations using stereospecific analysis of tramadol and its demethylated (M1 and M5) metabolites.

OBJECTIVE: To assess bioequivalence of two once-daily formulations of tramadol (T) as well as delineate pharmacokinetics of its enantiomers and those of its main metabolites after single- and multiple-dose administration. METHODS: Single- and multiple-dose studies were conducted separately each in 48 healthy volunteers using an open-label, randomized, crossover design. Subjects received the 200 mg test (Tramadolor) and reference (Ultram ER) formulations in a randomized manner separated by a 7-day washout period once (single-dose study) or once daily for 7 days (multiple-dose study). Blood was sampled on days 1-2 (single-dose) or days 4-7 (multiple-dose), and plasma samples were analyzed using a stereospecific assay for quantitation of individual enantiomers of T and its active O-demethylated (M1) and N,O-demethylated (M5) metabolites. Bioequivalence was assessed using log-transformation and 90% confidence intervals. RESULTS: All analytes showed stereoselectivity after single and multiple doses of both products, with average concentrations of (+)-T, (-)-M1, and (-)-M5 exceeding those of their respective antipode. However, a decrease in steady-state oral clearance of T relative to single dose was not stereoselective. In both studies, the formulations were bioequivalent with regard to AUG and Cmax for both enantiomers of all analytes. The Tmax for the reference (10-12 h) was significantly (p < 0.05) longer than that for the test (5-6 h). Degree of fluctuation of T enantiomers after the test was greater than the reference. Both formulations were tolerated relatively well. CONCLUSIONS: Tramadolor and Ultram ER were bioequivalent for both enantiomers of T, M1 and M5. It is unlikely there would be any significant clinical differences between the two formulations.

Stereospecific high-performance liquid chromatographic analysis of tramadol and its O-demethylated (M1) and N,O-demethylated (M5) metabolites in human plasma.

A stereospecific method for simultaneous quantitation of the enantiomers of tramadol (T) and its active metabolites O-demethyl tramadol (M1) and O-demethyl-N-demethyl tramadol (M5) in human plasma is reported. After the addition of penbutolol (IS), plasma (0.5 ml) samples were extracted into methyl tert-butyl ether, followed by back extraction into an acidic solution. The separation was achieved using a Chiralpak AD column with a mobile phase of hexanes:ethanol:diethylamine (94:6:0.2) and a flow rate of 1 ml/min. The fluorescence of analytes was then detected at excitation and emission wavelengths of 275 and 300 nm, respectively. All the six enantiomeric peaks of interest plus three unknown metabolite peaks and IS peak (a total of 10 peaks) eluted within 23 min, free from endogenous interference. The assay was validated in the plasma concentration range of 2.5-250 ng/ml, with a lower limit of quantitation of 2.5 ng/ml, for all the six analytes. The extraction efficiency (n=5) was close to 100% for both T and M1 enantiomers and 85% for M5 and IS enantiomers. The application of the assay was demonstrated by simultaneous measurement of plasma concentrations of T, M1, and M5 enantiomers in a healthy volunteer after the administration of 50 mg oral doses of racemic T.

Pharmacokinetics of a novel diltiazem HCl extended-release tablet formulation for evening administration.

A novel diltiazem HCl extended-release (ER) tablet formulation was developed for evening administration in the management of angina and hypertension. Pharmacokinetics of the formulation were evaluated to identify variations in morning (7 a.m. or 8 a.m.) versus evening (10 p.m.) drug administration. Single-dose (360 mg) and multiple-dose (360 mg once daily for 7 days), open-label, randomized, two-way crossover studies of the new diltiazem HCl ER tablets were completed in 48 healthy volunteers. Serial plasma samples were collected via direct venipuncture up to 48 hours postdose and analyzed for diltiazem and its two major metabolites by high-performance liquid chromatography (HPLC). The primary parameters used to assess the data were AUC0- infinity, AUC0-tau, AUC6 a.m.-12 p.m., Cmax, and tmax. Statistical comparisons using ANOVA were evaluated after logarithmic transformation of dose-dependent parameters. Diltiazem HCl ER tablets administered in the evening exhibited 17% and 22% greater bioavailability compared to morning administration under single-dose and steady-state conditions, respectively. The two times of drug administration were bioinequivalent in both studies. The evening schedule also provided more than twofold higher plasma diltiazem levels in the critical morning hours, when both blood pressure and the incidence of cardiovascular events are the highest.