Gail Murphy

Pharmacokinetics and pharmacodynamics of MK‐383, a selective non‐peptide platelet glycoprotein‐IIb/IIIa receptor antagonist, in healthy men

MK‐383 (L‐tyrosine, N‐n‐butylsulfonyl)‐O‐[4‐butyl(4‐piperidinyl)], monohydrochloride monohydrate) is a potent and specific platelet fibrinogen receptor antagonist that may be useful in preventing processes that lead to occlusive thrombus formation in the lumen of the blood vessel. Two placebo‐controlled phase I trials were completed in 56 healthy volunteers to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of MK‐383 administered as 1‐ and 4‐hour infusions in the presence and absence of aspirin. When administered to healthy male subjects by constant infusions up to 0.4 µg/kg/min over 1 hour or up to 0.2 µg/min over 4 hours, it provided a well‐tolerated reversible means of inhibiting platelet function. At infusion rates of 0.25 and 0.15 µg/kg/min for 1 and 4 hours, respectively, MK‐383 extended baseline bleeding time by 2.0‐ to 2.5‐fold and inhibited adenosine diphosphate (ADP)‐induced platelet aggregation by at least 80%. The pharmacokinetics of MK‐383 include a mean plasma clearance of 329 ml/min, steady‐state volume of distribution of 76 L, and half‐life of 1.6 hours. The percentage of dose excreted in the urine was 37%. Correlations between MK‐383 plasma concentration (C) and inhibition of platelet aggregation were examined by fitting with a sigmoid maximum‐effect model. The plasma concentration yielding 50% inhibition (C50) for MK‐383 in healthy volunteers is approximately 13 ng/ml, with a Hill coefficient >5. Based on a naive pooled analysis, an exponential empirical model best describes the MK‐383 C–extension of template bleeding time (BTE) relationship. The model indicates that the MK‐383 plasma concentration necessary to double BTE is approximately 30 ng/ml (i.e., 2.5‐fold greater than the C50 for ADP‐induced inhibition of platelet aggregation). The pharmacokinetics of MK‐383 was unaffected by pretreatment with 325 mg aspirin 1 day before and 1 hour before infusion. Conversely, aspirin pretreatment reduced C50 and increased bleeding time extension, suggesting that aspirin may have an additive effect with respect to inhibition of platelet function. Based on the putative role of the fibrinogen receptor in thrombotic processes and an acceptable human pharmacokinetic‐pharmacodynamic profile, MK‐383 should be evaluated in patients with unstable angina.

Effects of suvorexant, an orexin receptor antagonist, on sleep parameters as measured by polysomnography in healthy men.

STUDY OBJECTIVESnSuvorexant (MK-4305) is an orexin receptor antagonist being developed for the treatment of insomnia. This report describes the effects of nighttime administration of suvorexant on polysomnography (PSG) sleep parameters in healthy young men.nnnDESIGNnRandomized, double-blind, placebo-controlled, 4-period crossover PSG study, followed by an additional 5(th) period to assess pharmacokinetics.nnnSETTINGnSleep laboratory.nnnPARTICIPANTSnHealthy young men between 18 and 45 years of age (22 enrolled, 19 completed).nnnINTERVENTIONSnPeriods 1-4: suvorexant (10 mg, 50 mg, or 100 mg) or placebo 1 h before nighttime PSG recording. Period 5: suvorexant 10 mg, 50 mg, or 100 mg.nnnMEASUREMENTS AND RESULTSnIn Periods 1-4, overnight sleep parameters were recorded by PSG and next-morning residual effects were assessed by psychomotor performance tests and subjective assessments. Statistically significant sleep-promoting effects were observed with all doses of suvorexant compared to placebo. Suvorexant 50 mg and 100 mg significantly decreased latency to persistent sleep and wake after sleep onset time, and increased sleep efficiency. Suvorexant 10 mg significantly decreased wake after sleep onset time. There were no statistically significant effects of suvorexant on EEG frequency bands including delta (slow wave) activity based on power spectral analysis. Suvorexant was well tolerated. There was no evidence of next-day residual effects for suvorexant 10 mg. Suvorexant 50 mg statistically significantly reduced subjective alertness, and suvorexant 100 mg significantly increased reaction time and reduced subjective alertness. There were no statistically significant effects of any suvorexant dose on digit symbol substitution test performance. In Period 5, plasma samples of suvorexant were collected for pharmacokinetic evaluation. The median T(max) was 3 hours and apparent terminal t(½) was 9-13 hours.nnnCONCLUSIONSnIn healthy young men without sleep disorders, suvorexant promoted sleep with some evidence of residual effects at the highest doses.

Simvastatin Does Not Have a Clinically Significant Pharmacokinetic Interaction With Fenofibrate in Humans

Simvastatin and fenofibrate are both commonly used lipid‐regulating agents with distinct mechanisms of action, and their coadministration may be an attractive treatment for some patients with dyslipidemia. A 2‐period, randomized, open‐label, crossover study was conducted in 12 subjects to determine if fenofibrate and simvastatin are subject to a clinically relevant pharmacokinetic interaction at steady state. In treatment A, subjects received an 80‐mg simvastatin tablet in the morning for 7 days. In treatment B, subjects received a 160‐mg micronized fenofibrate capsule in the morning for 7 days, followed by a 160‐mg micronized fenofibrate capsule dosed together with an 80‐mg simvastatin tablet on days 8 to 14. Because food increases the bioavailability of fenofibrate, each dose was administered with food to maximize the exposure of fenofibric acid. The steady‐state pharmacokinetics (AUC0–24h, Cmax, and tmax) of active and total HMG‐CoA reductase inhibitors, simvastatin acid, and simvastatin were determined following simvastatin administration with and without fenofibrate. Also, fenofibric acid steady‐state pharmacokinetics were evaluated with and without simvastatin. The geometric mean ratios (GMRs) for AUC0–24h (80 mg simvastatin [SV] + 160 mg fenofibrate)/(80 mg simvastatin alone) and 90% confidence intervals (CIs) were 0.88 (0.80, 0.95) and 0.92 (0.82, 1.03) for active and total HMG‐CoA reductase inhibitors. The GMRs and 90% CIs for fenofibric acid (80 mg SV + 160 mg fenofibrate/160 mg fenofibrate alone) AUC0–24h and Cmax were 0.95 (0.88, 1.04) and 0.89 (0.77, 1.02), respectively. Because both the active inhibitor and fenofibric acid AUC GMR 90% confidence intervals fell within the prespecified bounds of (0.70, 1.43), no clinically significant pharmacokinetic drug interaction between fenofibrate and simvastatin was concluded in humans. The coadministration of simvastatin and fenofibrate in this study was well tolerated.

Effects of aprepitant on cytochrome P450 3A4 activity using midazolam as a probe.

Aprepitant is a neurokinin1 receptor antagonist that enhances prevention of chemotherapy‐induced nausea and vomiting when added to conventional therapy with a corticosteroid and a 5‐hydroxytryptamine3 (5‐HT3) antagonist. Because aprepitant may be used with a variety of chemotherapeutic agents and ancillary support drugs, which may be substrates of cytochrome P450 (CYP) 3A4, assessment of the potential of this drug to inhibit CYP3A4 activity in vivo is important. The effect of aprepitant on in vivo CYP3A4 activity in humans with oral midazolam used as a sensitive probe of CYP3A4 activity was evaluated in this study.

Aprepitant when added to a standard antiemetic regimen consisting of ondansetron and dexamethasone does not affect vinorelbine pharmacokinetics in cancer patients

PurposeAprepitant, a selective neurokinin-1 (NK-1) receptor antagonist approved for the treatment and prevention of emesis caused by moderately and highly emetogenic chemotherapy, is an inhibitor, inducer, and substrate of the cytochrome P450 3194 pathway. The CYP3A4 pathway is the major pathway of the metabolism of vinorelbine, a vinca alkaloid frequently used in combination with cisplatin. Therefore, we studied the potential interaction of the aprepitant 3-day antiemetic regimen on the pharmacokinetics of vinorelbine.Patients and methodsFourteen patients with metastatic solid tumors were included in this open-label, balanced, 2-period crossover study. In treatment arm A, vinorelbine (25xa0mg/m2xa0weekly) was administered alone, while in treatment arm B the same dose of vinorelbine was administered following the administration of the aprepitant antiemetic regimen on day 1 and alone on day 8. The antiemetic regimen of aprepitant was comprised of the following; on day 1: 125xa0mg aprepitant, 12xa0mg dexamethasone, and 32xa0mg ondansetron; on days 2 and 3: 80xa0mg aprepitant and 8xa0mg dexamethasone and on day 4: 8xa0mg dexamethasone. Blood samples for vinorelbine pharmacokinetic analysis were collected over 96xa0h.ResultsTwo patients discontinued the study due to adverse events that were judged not to be drug-related. Complete pharmacokinetic data of vinorelbine administered alone and with the aprepitant antiemetic regimen were obtained in 12 patients. The mean plasma concentration profile of vinorelbine administered with aprepitant was identical to that following vinorelbine administered alone, with geometric mean vinorelbine plasma AUC ratios of treatment B day 1/treatment A day 1 and of treatment B day 8/treatment A day of 1.01 (0.93, 1.10) and 1.00 (0.92, 1.08), respectively.ConclusionAs the aprepitant antiemetic regimen has no detectable inhibitory or inductive effect on the pharmacokinetics of vinorelbine, aprepitant when added to a standard antiemetic regimen consisting of ondansetron and dexamethasone can be safely combined with vinorelbine at clinically recommended doses.

Treatment with the Oral Growth Hormone Secretagogue MK-677 Increases Markers of Bone Formation and Bone Resorption in Obese Young Males†

The effect of 2 months of treatment with the oral growth hormone (GH) secretagogue MK‐677 on markers of bone metabolism was determined in healthy obese male subjects. This was a randomized, double‐blind, parallel, placebo‐controlled study. Twenty‐four healthy obese males, 19–49 years of age, with body mass index > 30 kg/m2 were treated with MK‐677 (25 mg/day; n = 12) or placebo (n = 12) for 8 weeks. MK‐677 increased markers of bone formation; a 23% increase in the carboxy‐terminal propeptide of type I procollagen levels and a 28% increase in procollagen III peptide levels were seen with as little as 2 weeks of MK‐677 treatment (p < 0.01 and p = 0.001 vs. placebo, respectively) while a 15% increase in serum levels of osteocalcin was not detected until 8 weeks of treatment (p < 0.01 vs. placebo). Markers of bone resorption were induced within 2 weeks of treatment with MK‐677; serum levels of the carboxy‐terminal cross‐linked telopeptide of type I collagen were increased 26% at 8 weeks (p = 0.001 vs. placebo), and urine hydroxyproline/creatinine and calcium/creatinine ratios at 8 weeks were increased by 23% (p < 0.05 vs. placebo) and 46% (p < 0.05 vs placebo), respectively. MK‐677 increased serum insulin‐like growth factor binding protein‐5 (IGFBP‐5) by 43–44% after 2–8 weeks of treatment (p < 0.01 vs. placebo). Serum IGFBP‐4 was increased by 25% after 2 weeks of treatment (p < 0.001 vs. placebo) but no significant change from baseline was observed after 8 weeks of treatment. Plasma interleukin‐6 was not significantly changed by active treatment. In conclusion, short‐term treatment of healthy obese male volunteers with the GH secretagogue MK‐677 increases markers of both bone resorption and formation. Large increases in serum levels of IGF‐I and IGFBP‐5 and a transient increase in serum IGFBP‐4 were found. Future long‐term studies are needed to investigate if prolonged treatment with MK‐677 increases bone mass.

Interaction of Single-Dose Ezetimibe and Steady-State Cyclosporine in Renal Transplant Patients

This open‐label, single‐period study evaluated the single‐dose pharmacokinetics of ezetimibe (EZE) 10 mg in the setting of steady‐state cyclosporine (CyA) dosing in renal transplant patients. A single 10‐mg dose of EZE was coadministered with the morning dose of CyA (75–150 mg twice a day). Total EZE (sum of unconjugated, parent EZE and EZE‐glucuronide; EZE‐total) AUC0‐last and Cmax were compared to values derived from a prespecified database of healthy volunteers. Geometric mean ratios (90% CIs) for (EZE + CyA)/EZE alone for EZE‐total AUC(0‐last) and Cmax were 3.41 (2.55, 4.56) and 3.91 (3.13, 4.89), respectively. Compared to healthy controls, EZE‐total AUC(0‐last) was 3.4‐fold higher in transplant patients receiving CyA; similar exposure levels were seen in a prior multiple‐dose study in which EZE 50 mg was administered to healthy volunteers without dose‐related toxicity. Because the long‐term safety implications of both higher EZE exposures and undetermined effect on CyA are not yet understood, the clinical significance of this interaction is unknown.

Effects of Ezetimibe on Cyclosporine Pharmacokinetics in Healthy Subjects

This single‐center, open‐label, 2‐period crossover study investigated the effects of multiple‐dose ezetimibe (EZE) on a single dose of cyclosporine (CyA). Healthy subjects received 2 treatments in random order with a 14‐day washout: (1) CyA 100 mg alone and (2) EZE 20 mg for 7 days with CyA 100 mg coadministered on day 7; EZE 20 mg alone was administered on day 8. AUC(0‐last) and Cmax geometric mean ratios (90% confidence interval) for ([CyA + EZE]/CyA alone) were 1.15 (1.07, 1.25) and 1.10 (0.97, 1.26), respectively. Tmax (∼1.3 hours) was similar with and without EZE (P >.200). Mean CyA exposure slightly increased (∼15%) with multiple‐dose EZE 20 mg; however, this value was contained within (0.80, 1.25). The implications for chronic EZE dosing within the usual clinical paradigm of chronic CyA dosing have not been established; caution is recommended when using these agents concomitantly. CyA concentrations should be monitored in patients receiving EZE and CyA.

Effects of oral administration of ibutamoren mesylate, a nonpeptide growth hormone secretagogue, on the growth hormone–insulin‐like growth factor I axis in growth hormone–deficient children

Ibutamoren mesylate (MK‐0677), an orally active nonpeptide growth hormone (GH) secretagogue, stimulates GH release through a pituitary and hypothalamic receptor that is different from the GH–releasing hormone receptor. We evaluated the safety and tolerability and the GH–insulin‐like growth factor (IGF) responses to two dosages of oral ibutamoren mesylate given to children with GH deficiency for 7 to 8 days. The patients, 18 prepubertal children (15 male, 3 female) with idiopathic GH deficiency, had a chronologic age of 10.6 ± 0.8 years (mean ± SD), bone age of 7.4 ± 0.7 years, growth velocity <10th percentile for age, height <10th percentile for age, and a maximum GH response of ≤10 μg/L to two different GH stimulation tests. The children were assigned as follows to one of three treatment groups with ibutamoren mesylate: 0.2 mg/kg per day for 7 days (days 1–7 or 8–14) and matching placebo for the alternate 7 days (groups I and II, respectively) or 0.8 mg/kg per day for 7 days (days 8–14, group III). On day 15 all patients received an 0.8‐mg/kg dose of ibutamoren mesylate. Patients in groups I and II were studied first to assess safety at the low dose before advancement to the high dose. Hormonal profiles were evaluated on day −1 (baseline) and day 15, and the results were expressed as the change from baseline within each group. After administration of ibutamoren mesylate 0.8 mg/kg for 8 days (group III), the median increases (on day 15) from baseline were as follows: 3.8 μg/L (range, 0 to 34.3) for serum GH peak concentration (P = .001), 4.3 μg · h/L (range, 1.3 to 35.6) for the GH area under the concentration‐time curve from time zero to 8 hours (AUC0–8) (P < .001), 12 μg/L (range, −4 to 116) for serum IGF‐I (P = .01), and 0.4 μg/L (range, −0.9 to 1.5) for serum IGF‐binding protein 3 (IGFBP‐3) (P = .01). There was no change in serum prolactin, glucose, triiodothyronine, thyroxine, thyrotropin, peak serum cortisol, and insulin concentrations or 24‐hour urinary free cortisol after administration of 0.8 mg/kg per day of ibutamoren mesylate for 8 days. We conclude that short‐term administration of ibutamoren mesylate can increase GH, IGF‐I, and IGFBP‐3 levels in some children with GH deficiency. Thus this compound is applicable for testing its effect on growth velocity.

Pharmacokinetics of oral dexamethasone and midazolam when administered with single-dose intravenous 150 mg fosaprepitant in healthy adult subjects.

Aprepitant or its prodrug fosaprepitant, in combination with a corticosteroid and a 5‐HT3 receptor antagonist, are used to prevent chemotherapy‐induced nausea and vomiting. This study evaluated the effect of fosaprepitant 150 mg on CYP3A4 metabolism. Fosaprepitant 150 mg has been submitted to regulatory agencies for consideration of approval as a single‐day alternative to the 3‐day oral aprepitant antiemetic regimen currently marketed. Part 1 of the study evaluated the drug interaction between fosaprepitant 150 mg and oral dexamethasone (8 mg daily for 3 days). Part 2 of the study evaluated the drug interaction between fosaprepitant 150 mg and oral midazolam (2 mg on days 1 and 4). Thirteen subjects were enrolled in part 1 and 10 in part 2. For dexamethasone, fosaprepitant increased the area under the plasma concentration—time curve from 0 to 24 hours by approximately 2.0‐fold on days 1 and 2 and to a lesser extent (∼1.2‐fold) on day 3. Similarly, for midazolam, fosaprepitant increased the area under the plasma concentration—time curve from 0 hours to infinity by approximately 1.8‐fold on day 1 but had no effect on midazolam pharmacokinetics on day 4. Fosaprepitant 150 mg is a weak inhibitor of CYP3A4. Oral dexamethasone doses on days 1 and 2 should be reduced by approximately 50% when coadministered with intravenous fosaprepitant 150 mg on day 1.