Diclofenac is a nonsteroidal anti-inflammatory drug (NSAID) of the phenylacetic acid class with anti-inflammatory, analgesic, and antipyretic properties. Contrary to the action of many traditional NSAIDs, diclofenac inhibits cyclooxygenase (COX)-2 enzyme with greater potency than it does COX-1. Similar to other NSAIDs, diclofenac is associated with serious dose-dependent gastrointestinal, cardiovascular, and renal adverse effects. Since its introduction in 1973, a number of different diclofenac-containing drug products have been developed with the goal of improving efficacy, tolerability, and patient convenience. Delayed- and extended-release forms of diclofenac sodium were initially developed with the goal of improving the safety profile of diclofenac and providing convenient, once-daily dosing for the treatment of patients with chronic pain. New drug products consisting of diclofenac potassium salt were associated with faster absorption and rapid onset of pain relief. These include diclofenac potassium immediate-release tablets, diclofenac potassium liquid-filled soft gel capsules, and diclofenac potassium powder for oral solution. The advent of topical formulations of diclofenac enabled local treatment of pain and inflammation while minimizing systemic absorption of diclofenac. SoluMatrix diclofenac, consisting of submicron particles of diclofenac free acid and a proprietary combination of excipients, was developed to provide analgesic efficacy at reduced doses associated with lower systemic absorption. This review illustrates how pharmaceutical technology has been used to modify the pharmacokinetic properties of diclofenac, leading to the creation of novel drug products with improved clinical utility.

Retrospectively, effects of long-term therapy with clozapine were evaluated in 121 out-patients. They were treated for 32 +/- 43 months in a daily dosage of 131 +/- 99 mg. Sixty nine patients were schizophrenic and had previously received one or more neuroleptics but with insufficient response or severe side effects. Nine patients suffered from tardive dyskinesia (TD), 44 patients had other diagnoses. Twenty two per cent of the schizophrenic patients improved slightly, 65% markedly and in 13% the symptoms nearly totally disappeared. Fourty per cent of chronic schizophrenics showed improvement of anergia. Eleven per cent of the patients with TD did not improve, 22% showed slight and 67% marked improvement. Clinically relevant side-effects occurred in 64% of patients: Generally sedation/hypotension, EG and ECG alterations, changes of white blood cell count, increase of liver enzymes and weight gain. EEG alteration correlated significantly with dosage of clozapine (P less than 0.01). In 6% of patients, severe side-effects led to discontinuation of clozapine treatment. No case of agranulocytosis occurred. Most patients tolerated the drug well and were compliant. Under careful control of hematological and other variables, the benefit/risk ratio of clozapine long-term treatment appears to be high and acceptable.

Background and ObjectiveAbiraterone acetate is approved for the treatment of metastatic castration-resistant prostate cancer. The originator abiraterone acetate (OAA) formulation is poorly absorbed and exhibits large pharmacokinetic variability in abiraterone exposure. Abiraterone acetate fine particle (AAFP) is a proprietary formulation (using SoluMatrix Fine Particle Technology™) designed to increase the oral bioavailability of abiraterone acetate. Here, we report on two phase I studies in healthy male subjects aged 18–50 years.MethodsIn Study 101, 20 subjects were randomized in a crossover design to single doses of AAFP 100, 200, or 400 mg or OAA 1000 mg taken orally under fasting conditions. Results suggested that AAFP 500 mg would be bioequivalent to OAA 1000 mg in the fasted state. To confirm the bioequivalence hypothesis and to further expand the AAFP dose range, in Study 102, 36 subjects were randomized in a crossover design to single doses of AAFP 125, 500, or 625 mg or OAA 1000 mg. Both studies included a 7-day washout period between administrations.ResultsDose-dependent increases in the area under the plasma concentration–time curve and maximum plasma concentration with AAFP were observed in both studies. The AAFP 500-mg bioavailability relative to OAA 1000 mg measured by the geometric mean ratio for area under the plasma concentration–time curve from time zero to the time of the last quantifiable concentration was 93.4% (90% confidence interval 85.3–102.4), area under the plasma concentration–time curve from time zero to infinity was 91.0% (90% confidence interval 83.3–99.4), and maximum plasma concentration was 99.8% (90% confidence interval 86.3–115.5). Dose proportionality was seen across all AAFP dose levels (100–625 mg). Abiraterone acetate fine particle was found to be safe and well tolerated in this study.ConclusionAbiraterone acetate fine particle 500 mg was demonstrated to be bioequivalent to OAA 1000 mg in healthy volunteers under fasted conditions.Electronic supplementary materialThe online version of this article (doi:10.1007/s40262-017-0536-2) contains supplementary material, which is available to authorized users.

Therapeutic equivalence between AAFP 500mg daily and OAA 1000mg daily based on serum testosterone levels was confirmed in mCRPC patients. Both agents led to similar PSA-50 response rates. Abiraterone trough levels were similar between treatments. No new safety concerns were observed.

Purpose The originator abiraterone acetate (OAA) formulation is used for the treatment of metastatic castration-resistant prostate cancer (mCRPC). This study evaluated the bioavailability and bioequivalence of a novel formulation, abiraterone acetate fine particle (AAFP), versus OAA on a steady-state background of steroids.MethodsThirty-seven healthy male subjects were randomized in a crossover design to receive methylprednisolone (4 mg twice daily) or prednisone (5 mg twice daily) for 12 days in Period 1. On Day 11 of Period 1, subjects given methylprednisolone received a single dose of AAFP 500 mg, and subjects given prednisone received a single dose of OAA 1000 mg under fasted conditions. After a 2-week steroid washout period, subjects received the alternate treatments in Period 2.ResultsThere were no statistical differences regarding area under the curve (AUC) and maximum concentration (C max) between AAFP and OAA. The bioavailability of abiraterone from AAFP versus OAA by geometric mean ratio was AUC0–∞, 95.9% (90% confidence interval [CI] 86.0–106.9); AUC0–t, 99.2% (88.7–110.9); and C max, 116.8% (102.2–133.4). The coefficient of variation (CV) was smaller for AAFP versus OAA (AUC0–∞, CV 44.23 vs. 55.61%; AUC0–t, 45.17 vs. 58.16%; C max, 54.55 vs. 65.65%, respectively). Both treatments were safe and well tolerated.ConclusionsAAFP plus methylprednisolone provided abiraterone exposure that was comparable to OAA plus prednisone with respect to C max and AUC. Less drug exposure variability was observed with AAFP compared with OAA. Reduced pharmacokinetic variability may positively influence clinical outcomes and warrants further study in mCRPC patients.

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e606 Background: AA is approved for treatment of metastatic castration-resistant prostate cancer (mCRPC). In healthy subjects administered the originator AA (OAA) formulation, AUC and Cmaxincreased by 10- and 17-fold, respectively, when administered after a high-fat meal relative to the fasted state.1 AAFP is a proprietary formulation (utilizing SoluMatrix Fine-Particle Technology) of AA designed to improve the oral bioavailability (BA) of AA, and to potentially reduce food effects compared with the OAA formulation. In healthy subjects, AAFP 500 mg was established as bioequivalent to OAA 1000 mg in a prior study when taken in fasted conditions. Methods: Healthy male subjects (N = 25) fasted 10-h overnight before randomization in a crossover design to a single 500 mg dose of AAFP under fasted or fed (high-fat FDA breakfast 30 min before AAFP administration) conditions. There was a 7-day washout period prior to crossover; 22 subjects completed the study. Results: Drug exposure of AAFP 500 mg was significantly ( P< 0.0001) greater under fed vs fasted conditions (Table). Following a single dose of AAFP 500 mg, relative BA measured by the ratio of test-to-reference geometric means of AUC and Cmax of abiraterone indicated that drug exposure increased under fed conditions by approximately 4.5- and 6.5-fold, respectively, vs under fasted conditions. AAFP 500 mg was safe and well-tolerated under fed or fasted conditions. Conclusions: AAFP 500 mg under fed conditions has higher BA than under fasted conditions. A direct comparative study between AAFP 500 mg and OAA 1000 mg under restricted food conditions is underway in patients with mCRPC. 1US FDA. CDER. Abiraterone Acetate NDA 202379 Review, 2010. Clinical trial information: NCT02737332. [Table: see text]

e605 Background: AA is approved for treatment of metastatic castration-resistant prostate cancer. The originator AA (OAA) formulation is poorly absorbed and exhibits large pharmacokinetic variability in abiraterone exposure in healthy subjects. AA fine particle (AAFP) is a proprietary formulation (utilizing SoluMatrix Fine-Particle Technology) that was designed to provide improved BA versus the OAA formulation. Methods: In Study 1, 20 subjects were randomized in a crossover design to single doses of AAFP 100, 200, or 400 mg or OAA 1000 mg. To further expand the AAFP dose range, 36 subjects were randomized in a crossover design to AAFP 125, 500, or 625 mg or OAA 1000 mg in Study 2. Both studies included a 7-day washout period prior to crossover. Results: AAFP 500 mg BA relative to OAA 1000 mg measured by the ratio of test-to-reference geometric means was AUC0-t 93.4% (90% CI: 85.3–102.4%), AUC0-∞ 91.0% (90% CI: 83.3–99.4%), and Cmax99.8% (90% CI: 86.3–115.5%). Dose proportionality was seen across all AAFP dose levels (see table). Between-subject variability for AAFP 500 and 625 mg was similar to OAA 1000 mg. No significant AAFP-related adverse events (AEs), serious AEs, or deaths occurred. Treatment-emergent AEs were mostly Grade 1. Conclusions: AAFP demonstrated improved BA and AAFP 500 mg was bioequivalent to OAA 1000 mg in healthy male volunteers under single dose and fasted conditions. AAFP showed dose proportionality across all doses studied (100–625 mg). Clinical trial information: NCT02737332. [Table: see text]