Evaluation of a Low-Fat Low-Calorie Meal on the Relative Bioavailability of Trametinib and Dabrafenib: Results From a Randomized, Open-Label, 2-Part Study in Healthy Participants.

In this randomized, open-label, 2-part, 2 × 2 crossover, phase 1 study, the effect of a low-fat low-calorie (LFLC) meal on the relative bioavailability of a trametinib 2-mg tablet or dabrafenib 150-mg capsule was evaluated in healthy participants. Trametinib adjusted geometric mean ratios (90%CI) of fed : fasted for area under the concentration-time curve (AUC) from time 0 to the last quantifiable concentration and AUC from time 0 extrapolated to infinity were 0.76 (0.71-0.82) and 0.82 (0.77-0.88), respectively. For dabrafenib, the adjusted geometric mean ratios of AUC from time 0 to the last quantifiable concentration and AUC from time 0 extrapolated to infinity (90%CI) for fed:fasted were 0.85 (0.79-0.91) and 0.86 (0.80-0.92), respectively. Consumption of an LFLC meal delayed trametinib and dabrafenib absorption, with an increase in time to maximum concentration of ≈15 and ≈30 minutes, respectively, compared to the fasted state. These findings indicate that consumption of an LFLC meal reduced the bioavailability and delayed the absorption of trametinib and dabrafenib, supporting current recommendations to administer both drugs in the fasting state; however, an occasional LFLC meal is unlikely to affect the pharmacokinetics of the drugs once steady state is reached and, by consequence, not likely to alter the overall intended efficacy.

Comparative Bioavailability of a Single Dose of Trametinib (TMT212) Containing 9% vs 11% Dimethyl Sulfoxide in Randomized Healthy Volunteers to Assess Long-Term Storage at Room Temperature.

Storage of trametinib tablets outside of 2-8°C protected from moisture may lead to loss of dimethyl sulfoxide (DMSO) and adversely impact trametinib bioavailability. In this open-label, phase 1, single-dose, randomized, 2-treatment, 2-period crossover study in healthy volunteers, bioavailability of a single 2-mg tablet of trametinib containing 9% DMSO (test formulation), corresponding to the lowest DMSO content in the tablet after storage at 25°C for 36 months, was evaluated vs bioavailability of a 2-mg tablet containing 11% DMSO (reference formulation). Sixty-five percent of subjects (n = 39/65) were men, and mean (standard deviation) age was 45.6 (11.17) years. Time to reach maximum plasma concentration occurred at 1.5 hours after dosing. The geometric mean ratio (90%CI) comparing 2-mg trametinib containing 9% DMSO with 2-mg trametinib containing 11% DMSO for area under the concentration-time curve from time 0 to the last measurable plasma concentration sampling time was 0.890 (0.848-0.935), suggesting the 2 formulations have similar bioavailability. The majority of adverse events were mild, with 1 subject experiencing 1 grade 3 headache. These results indicated that storage of trametinib at room temperatures ≤25°C during the overall shelf life of 36 months would not negatively impact trametinib bioavailability.

Safety and efficacy of nazartinib (EGF816) in adults with EGFR-mutant non-small-cell lung carcinoma: a multicentre, open-label, phase 1 study.

BACKGROUND: Resistance to first-generation and second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is mediated by the emergence of the Thr790Met mutation in 50-60% of treated patients with non-small-cell lung cancer (NSCLC). We aimed to assess the safety and activity of nazartinib (EGF816), a third-generation EGFR TKI that selectively inhibits EGFR with Thr790Met or activating mutations (or both), while sparing wild-type EGFR, in patients with advanced EGFR-mutant NSCLC. METHODS: This phase 1 dose-escalation part of an open-label, multicentre, phase 1/2 study was conducted at nine academic medical centres located in Europe, Asia, and North America. Patients were included if they were aged 18 years or older and had stage IIIB-IV EGFR-mutant NSCLC (with varying statuses of EGFR mutation and previous therapy allowed), at least one measurable lesion, and an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less. Nazartinib (at seven dose levels between 75 mg and 350 mg, in capsule or tablet form) was administered orally, once daily, on a continuous 28-day dosing schedule. A two-parameter Bayesian logistic regression model, guided by the escalation with overdose control principle, was implemented to make dose recommendations and estimate the maximum tolerated dose or recommended phase 2 dose of nazartinib (the primary outcome). This study is registered with ClinicalTrials.gov (NCT02108964); enrolment to phase 1 is complete and the study is ongoing. FINDINGS: By Aug 31, 2017, 180 patients (116 [64%] women; median age 60 years (52-69); 116 [64%] with ECOG performance status 1) received nazartinib across seven dose levels: 75 mg (n=17), 100 mg (n=38), 150 mg (n=73), 200 mg (n=8), 225 mg (n=28), 300 mg (n=5), and 350 mg (n=11). Seven dose-limiting toxicities were observed in six (3%) patients who received 150 mg, 225 mg, or 350 mg nazartinib once daily. Although the maximum tolerated dose was not met, the recommended phase 2 dose was declared as 150 mg once daily (tablet). The most common adverse events, regardless of cause, were rash (all subcategories 111 [62%] patients, maculopapular rash 72 [40%], dermatitis acneiform 22 [12%]), diarrhoea (81 [45%]), pruritus (70 [39%]), fatigue (54 [30%]), and stomatitis (54 [30%]), and were mostly grades 1-2. Any-cause grade 3-4 adverse events were reported in 99 (55%) patients across all doses, the most common being rash (all subcategories grouped 27 [15%]), pneumonia (12 [7%]), anaemia (ten [6%]), and dyspnoea (nine [5%]). Serious adverse events suspected to be drug-related occurred in 16 (9%) patients. INTERPRETATION: Nazartinib has a favourable safety profile, with low-grade skin toxicity characterised by a predominantly maculopapular rash that required minimal dose reductions. FUNDING: Novartis Pharmaceuticals Corporation.

Pharmacokinetics and antitumor activity of patupilone combined with midazolam or omeprazole in patients with advanced cancer.

PURPOSE: Patupilone is a novel microtubule-targeting cytotoxic agent with potential interaction with CYP3A4/CYP2C19 enzymes. Midazolam and omeprazole are primarily metabolized by CYP3A4 and CYP2C19, respectively. We evaluated the inhibitory effects of patupilone on the CYP3A4/CYP2C19 pathways. METHODS: This study had 2 parts: in an initial core phase, patients were randomly assigned to receive midazolam 4 mg or omeprazole 40 mg PO (days 1 and 29) and patupilone 10 mg/m(2) IV (days 8 and 29). Patients without progression continued patupilone every 3 weeks until disease progression or unacceptable toxicity (extension phase). RESULTS: Forty-six patients were treated. The areas under the concentration-time curves (AUC)s of midazolam with or without patupilone co-administration were similar. The C (max) of midazolam when co-administered with patupilone was highly variable and was lower compared with midazolam alone; however, the oral clearance and terminal half-lives were similar. Both the C (max) and AUC of omeprazole when co-administered with patupilone were highly variable and lower than with omeprazole alone. However, the oral clearance and terminal half-lives were similar. The latter data suggest that patupilone decreased the absorption of omeprazole (by ~20%). The overall safety profile was consistent with that of previous single-agent patupilone studies; 2 partial responses (ovarian and pancreatic cancer) and 1 complete response (serous ovarian adenocarcinoma) were observed. CONCLUSIONS: Patupilone was not a potent CYP3A4 or CYP2C19 inhibitor. No dose adjustment is required when omeprazole or midazolam is used in patients treated with patupilone. Patupilone exhibited promising antitumor activity in heavily pretreated patients with ovarian and pancreatic cancer.

Effects of imatinib mesylate on the pharmacokinetics of paracetamol (acetaminophen) in Korean patients with chronic myelogenous leukaemia.

AIMS: The major objective of the present study was to investigate the effect of imatinib on the pharmacokinetics of paracetamol in patients with chronic myelogenous leukaemia (CML). METHODS: Patients (n = 12) received a single oral dose of acetaminophen 1000 mg on day 1 (control). On days 2-8, imatinib 400 mg was administered daily. On day 8 (treatment), another 1000 mg dose of paracetamol was administered 1 h after the morning dose of imatinib 400 mg. Blood and urine samples were collected for bioanalytical analyses. RESULTS: The area under the plasma concentration-time curve (AUC) for paracetamol, paracetamol glucuronide and paracetamol sulphate under control conditions was similar to that after treatment with imatinib; the 90% confidence interval of the log AUC ratio was within 0.8 to 1.25. Urinary excretion of paracetamol, paracetamol glucuronide and paracetamol sulphate was also unaffected by imatinib. The pharmacokinetics of paracetamol and imatinib in Korean patients with CML were similar to previous pharmacokinetic results in white patients with CML. Co-administration of a single dose of paracetamol and multiple doses of imatinib was well tolerated and safety profiles were similar to those of either drug alone. CONCLUSIONS: The pharmacokinetics of paracetamol and its major metabolites in the presence of imatinib were similar to those of the control conditions and the combination was well tolerated. These findings suggest that imatinib can be safely administered with paracetamol without dose adjustment of either drug.

Pharmacokinetics, metabolism, and excretion of anacetrapib, a novel inhibitor of the cholesteryl ester transfer protein, in rats and rhesus monkeys.

The pharmacokinetics and metabolism of anacetrapib (MK-0859), a novel cholesteryl ester transfer protein inhibitor, were examined in rats and rhesus monkeys. Anacetrapib exhibited a low clearance in both species and a moderate oral bioavailability of approximately 38% in rats and approximately 13% in monkeys. The area under the plasma concentration-time curve in both species increased in a less than dose-proportional manner over an oral dose range of 1 to 500 mg/kg. After oral administration of [(14)C]anacetrapib at 10 mg/kg, approximately 80 and 90% of the radioactive dose was recovered over 48 h postdose from rats and monkeys, respectively. The majority of the administered radioactive dose was excreted unchanged in feces in both species. Biliary excretion of radioactivity accounted for approximately 15% and urinary excretion for less than 2% of the dose. Thirteen metabolites, resulting from oxidative and secondary glucuronic acid conjugation, were identified in rat and monkey bile. The main metabolic pathways consisted of O-demethylation (M1) and hydroxylation on the biphenyl moiety (M2) and hydroxylation on the isopropyl side chain (M3); these hydroxylations were followed by O-glucuronidation of these metabolites. A glutathione adduct (M9), an olefin metabolite (M10), and a propionic acid metabolite (M11) also were identified. In addition to parent anacetrapib, M1, M2, and M3 metabolites were detected in rat but not in monkey plasma. Overall, it appears that anacetrapib exhibits a low-to-moderate degree of absorption after oral dosing and majority of the absorbed dose is eliminated via oxidation to a series of hydroxylated metabolites that undergo conjugation with glucuronic acid before excretion into bile.

Metabolism and excretion of anacetrapib, a novel inhibitor of the cholesteryl ester transfer protein, in humans.

Anacetrapib is a novel cholesteryl ester transfer protein inhibitor being developed for the treatment of primary hypercholesterolemia and mixed dyslipidemia. The absorption, distribution, metabolism, and excretion of anacetrapib were investigated in an open-label study in which six healthy male subjects received a single oral dose of 150 mg and 165 microCi of [(14)C]anacetrapib. Plasma, urine, and fecal samples were collected at predetermined times for up to 14 days postdose and were analyzed for total radioactivity, the parent compound, and metabolites. The majority of the administered radioactivity (87%) was eliminated by fecal excretion, with negligible amounts present in urine (0.1%). The peak level of radioactivity in plasma (approximately 2 microM equivalents of [(14)C]anacetrapib) was achieved approximately 4 h postdose. The parent compound was the major radioactive component (79-94% of total radioactivity) in both plasma and feces. Three oxidative metabolites, M1, M2, and M3, were detected in plasma and feces and were identified as the O-demethylated species (M1) and two secondary hydroxylated derivatives of M1 (M2 and M3). Each metabolite was detected at low levels, representing

Discovery of 4-heteroarylbicyclo[2.2.2]octyltriazoles as potent and selective inhibitors of 11beta-HSD1: novel therapeutic agents for the treatment of metabolic syndrome.

Replacement of the pentyl chain on our original bicyclo[2.2.2]octyltriazole leads 1 and 2 has led to the discovery that heteroaryl substituted bicyclo[2.2.2]octyltriazoles are potent and selective 11beta-hydroxysteroid dehydrogenase type I (11beta-HSD1) inhibitors with excellent pharmacokinetic profiles.