Distribution, Metabolism, and Excretion of Gedatolisib in Healthy Male Volunteers After a Single Intravenous Infusion.

In this open-label study (NCT02142920), we investigated the distribution, pharmacokinetics, and metabolism of the pan-class-I isoform phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor gedatolisib (PF-05212384), following a single intravenous administration in healthy male subjects. A single, 89-mg, intravenous dose of gedatolisib was associated with a favorable safety profile in the 6 healthy subjects evaluated. Peak plasma concentrations for unchanged gedatolisib and total radioactivity were observed at the end of the 30-minute infusion. The only observed drug-related material in plasma was the parent drug, gedatolisib. Terminal half-life for plasma gedatolisib was ∼37 hours. Following the dose, 66%-73% of drug-related material was recovered in the feces. Metabolism of gedatolisib was trace; only 1 oxidative metabolite, M5, was identified in feces (<1% of total dose). Identification of gedatolisib in feces suggests that biliary and/or intestinal secretion of unchanged parent drug significantly contributes to gedatolisib clearance.

Evaluation of a Janus kinase 1 inhibitor, PF-04965842, in healthy subjects: A phase 1, randomized, placebo-controlled, dose-escalation study.

AIMS: To determine the safety, tolerability, pharmacokinetics and pharmacodynamics of the Janus kinase 1-selective inhibitor, PF-04965842. METHODS: This was a phase 1, first-in-human, randomized, double-blind, placebo-controlled, combination single- and multiple-dose escalation, parallel design study in healthy subjects (http://clinicaltrials.gov, NCT01835197). Subjects received a single dose of placebo or 3, 10, 30, 100, 200, 400 or 800 mg PF-04965842 (single ascending dose phase) and placebo or 30 mg once daily (QD), 100 mg QD, 200 mg QD, 400 mg QD, 100 mg twice daily (BID) or 200 mg BID PF-04965842 for 10 consecutive days (multiple ascending dose phase). The primary objective was to determine the safety and tolerability of PF-04965842. RESULTS: Seventy-nine subjects were randomized and received study treatments. There were no deaths or serious adverse events. The most frequent treatment-emergent adverse events were headache (n = 13), diarrhoea (n = 11) and nausea (n = 11). PF-04965842 was absorbed rapidly (median time at which maximum plasma concentration occurred generally ≤1 h following either single- or multiple-dose administration) and eliminated rapidly (mean t½ 2.8-5.2 h after 10 days of QD or BID administration in the multiple ascending dose phase). Increases in maximum plasma concentration and area under the concentration-time curve were dose proportional up to 200 mg (single or total daily doses) with an apparent trend towards greater than proportional increases with higher doses. Less than 4.4% of the dose was recovered unchanged in urine. Changes in pharmacodynamic biomarkers were consistent with the known effects of Janus kinase signalling inhibition. CONCLUSIONS: These results support further evaluation of PF-04965842 for clinical use in patients with inflammatory diseases.

Evaluation of the Effect of Tofacitinib on the Pharmacokinetics of Oral Contraceptive Steroids in Healthy Female Volunteers.

Tofacitinib is an oral Janus kinase inhibitor. Tofacitinib metabolism is primarily mediated by cytochrome P450 3A4. This phase 1 randomized, open-label, 2-way crossover study (NCT01137708) evaluated the effect of tofacitinib 30 mg twice daily on the single-dose pharmacokinetics of combination oral contraceptives ethinylestradiol (EE) and levonorgestrel (LN). EE and LN were administered as a single Microgynon 30® tablet (30 µg EE and 150 µg LN) to 19 healthy women. In the presence of tofacitinib, the area under the curve from time zero to infinity (AUC∞ ) increased by 6.6% and 0.9% for EE and LN, respectively. Maximal plasma concentrations decreased by 10.4% for EE and increased by 12.2% for LN when coadministered with tofacitinib. The 90% confidence intervals for the adjusted geometric mean ratios for AUC∞ fell within the 80%-125% region for both EE and LN. Mean half-life was similar in the presence and absence of tofacitinib: 13.8 and 13.3 hours, respectively, for EE; 25.9 and 25.4 hours, respectively, for LN. Tofacitinib had no clinically relevant net inhibitory or inductive effect on the pharmacokinetics of EE and LN. Therefore, there is no evidence to suggest dose adjustments of oral contraceptive drugs containing EE or LN when coadministered with tofacitinib.

The Pharmacokinetics of Pregabalin in Breast Milk, Plasma, and Urine of Healthy Postpartum Women.

BACKGROUND: Limited data exist on the presence of pregabalin in human breast milk of nursing mothers. OBJECTIVES: This study aimed to determine pregabalin concentrations in breast milk, estimate the infant daily pregabalin dose from nursing mothers, and evaluate pregabalin pharmacokinetic data in lactating women (≥ 12 weeks postpartum). METHODS: In this multiple-dose, open-label, pharmacokinetic study, 4 doses of pregabalin 150 mg were administered orally at 12-hour intervals. Urine, blood, and breast milk samples were collected up to 12, 24, and 48 hours, respectively, following the fourth dose. Pharmacokinetic parameters were estimated using noncompartmental methods. Adverse events were monitored throughout. RESULTS: Ten healthy lactating women (age 24-37 years) received pregabalin. Geometric mean pregabalin Cmaxss and AUCτ values in breast milk were approximately 53% and 76%, respectively, of those for plasma. The mean amount of pregabalin in breast milk recovered in a 24-hour period after the last dose was 574 µg (range, 270-1720 µg), which is approximately 0.2% of the administered daily maternal dose of 300 mg. The estimated average daily infant dose of pregabalin from breast milk was 0.31 mg/kg/day, which would be approximately 7% (23% coefficient of variation) of the body weight normalized maternal dose. Approximately 89% of the dose administered was recovered in urine. Renal clearance averaged 68.2 mL/min. Adverse events were of mild or moderate severity. CONCLUSION: Lactation appears to have had little influence on pregabalin pharmacokinetics. Overall, the estimated dose of pregabalin in breastfed children of women receiving pregabalin is low. Pregabalin was well tolerated in lactating women. DECLARATION OF CONFLICTING INTERESTS: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Peter A. Lockwood, Lynne Pauer, Joseph M. Scavone, Maud Allard, Laure Mendes da Costa, Tanja Alebic-Kolbah, Anna Plotka, Christine W. Alvey, and Marci L. Chew were all full-time employees of Pfizer at the time the study was completed and hold stock and/or stock options in Pfizer. FUNDING: The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was sponsored by Pfizer, which was involved in the study design, the collection, analysis, and interpretation of the data, the writing of the report, and the decision to submit the paper for publication. Medical writing support was provided by Penny Gorringe, MSc, of Engage Scientific Solutions and funded by Pfizer.

Effect of the gastrointestinal prokinetic agent erythromycin on the pharmacokinetics of pregabalin controlled-release in healthy individuals: a phase I, randomized crossover trial.

BACKGROUND AND OBJECTIVES: The controlled-release (CR) formulation of pregabalin is designed to remain in the stomach for a prolonged period while slowly releasing pregabalin for absorption in the small intestine. This study evaluated the effect of the gastrointestinal prokinetic agent, erythromycin, on the pharmacokinetics of a single dose of pregabalin CR 330 mg administered following an evening meal and the safety and tolerability of a single dose of pregabalin CR 330 mg when administered with and without multiple doses of erythromycin 500 mg. METHODS: This was a phase I, open-label, randomized, two-period, two-treatment crossover study. Participants received (in a randomized sequence) a single oral dose of pregabalin CR 330 mg alone and pregabalin CR 330 mg co-administered with multiple doses of erythromycin 500 mg. The CR formulation was administered immediately following a standardized 600-750 calorie 30 % fat evening meal. Erythromycin 500 mg was administered orally approximately 1 h prior to pregabalin CR, as well as 6 and 12 h following the first erythromycin dose. Blood samples were collected up to 48 h post-pregabalin CR dose. Pharmacokinetic parameters were estimated from concentration-time data using standard noncompartmental methods. Adverse events were monitored throughout. RESULTS: Eighteen healthy participants (aged 19-52 years) received pregabalin CR. Co-administration of pregabalin CR with erythromycin resulted in a 17 % decrease in total exposure [area under the plasma concentration-time curve from zero to infinity (AUC∞)] and a 13 % decrease in peak plasma concentrations (C max) relative to pregabalin CR administered alone. The 90 % CI for the ratio of the adjusted geometric mean AUC∞ was 76.5-89.2 % (outside the 80-125 % range prespecified for bioequivalence). Adverse events were of mild to moderate severity and the adverse event profile was similar for pregabalin CR administered with and without erythromycin. CONCLUSION: Co-administration of multiple high doses of erythromycin resulted in 17 % lower pregabalin exposure for a single dose of pregabalin CR 330 mg than for pregabalin CR 330 mg administered alone. Although the two treatments did not achieve formal bioequivalence, the impact of co-administered erythromycin treatment was small and not considered clinically relevant.

Single- and multiple-dose pharmacokinetics of tofacitinib in healthy Chinese volunteers.

Tofacitinib is an oral Janus kinase inhibitor. The objective of this phase 1, open-label study was to characterize the single- and multiple-dose pharmacokinetics (PK) of tofacitinib in 12 healthy, adult Chinese volunteers. Eligible subjects received oral tofacitinib 10 mg once daily on days 1 and 6 and twice daily on days 2-5. Blood samples were collected on day 1 predose and over 24 hours postdose (day 2 predose), predose on days 3-6, and over 12 hours postdose on day 6. PK parameters were calculated using noncompartmental analysis. Mean concentration-time profiles for days 1 and 6 were similar, with median time to peak concentration of 0.5 hours on both days. Plasma concentrations declined rapidly following attainment of peak concentrations, with a mean terminal half-life of 3.3 hours on day 1 (single dose) and 2.5 hours on day 6 (multiple dose). No accumulation in plasma occurred with twice-daily administration: accumulation ratio of 1.04. The rapid absorption, elimination, and systemic exposures (peak and area under the concentration-time curve) observed in healthy Chinese volunteers in this study are similar to those previously reported in white subjects.

Safety, tolerability, and pharmacokinetics of pregabalin in children with refractory partial seizures: a phase 1, randomized controlled study.

OBJECTIVE: To evaluate the safety, tolerability, and pharmacokinetics (PK) of pregabalin as adjunctive therapy in children with refractory partial seizures. METHODS: This was a phase 1, randomized, placebo-controlled, parallel-group, escalating-dose, multiple-dose study comprising a 7-day, double-blind treatment period and a single-blind, single dose of pregabalin administered to all children on day 8. Children in four age cohorts (1-23 months, 2-6, 7-11, and 12-16 years) received one of four doses of pregabalin (2.5, 5, 10, or 15 mg/kg/day) or placebo. Safety and tolerability were assessed throughout the study. Steady-state and single-dose PK parameters on day 8 were analyzed using standard noncompartmental procedures. RESULTS: Sixty-five children received at least one dose of treatment. Four pregabalin-treated children discontinued treatment, three of whom received 15 mg/kg/day. Two children experienced serious adverse events, one of whom received pregabalin 15 mg/kg/day. During double-blind treatment, the most common adverse events reported in the pregabalin-treated population were somnolence (27.1%) and dizziness (12.5%). Steady-state pregabalin peak and total exposure in each age cohort appeared to increase linearly with dose. Apparent oral clearance (CL/F) was directly related to creatinine clearance, consistent with adults. CL/F normalized for body weight was 43% higher in patients weighing <30 kg. Steady-state and single-dose PK were consistent. SIGNIFICANCE: Pregabalin at doses up to 10 mg/kg/day in children aged 1 month to 16 years, and at doses up to 15 mg/kg/day in those aged <6 years, demonstrated acceptable safety and tolerability. For children weighing <30 kg, a dose increase of 40% (mg/kg dosing) is required to achieve comparable exposure with adults or children weighing ≥30 kg. These data will inform dose selection in phase 3 trials of the efficacy and safety of adjunctive pregabalin in children with refractory partial seizures.

Pharmacokinetics of pregabalin controlled-release in healthy volunteers: effect of food in five single-dose, randomized, clinical pharmacology studies.

BACKGROUND: The pharmacokinetic properties of the immediate-release (IR) and the recently developed controlled-release (CR) formulation of pregabalin are dose proportional. Pregabalin IR can be taken with or without food. OBJECTIVES: This analysis characterizes the effect of food on pregabalin CR. The objectives of this analysis were: (1) to evaluate the effect of administration time and fat or caloric content of an accompanying meal on the pharmacokinetic properties of a single dose of pregabalin CR (330 mg) relative to a single dose of pregabalin IR (300 mg); (2) to evaluate the pharmacokinetic properties of a single dose of pregabalin CR administered fasted relative to a single dose of pregabalin CR administered immediately after food; and (3) to determine the safety and tolerability of single-dose administration of pregabalin CR and IR with and without food. METHODS: The effect of food on the pharmacokinetic properties of pregabalin CR was determined in five phase I, open-label, single-dose, crossover studies (24-28 participants/study). Caloric and fat content of meals were varied and treatments were administered in the morning, at midday, or in the evening. Blood samples were collected up to 48 h post-dose. Pharmacokinetic parameters were estimated from plasma concentration-time data using standard noncompartmental methods. Adverse events were monitored throughout all studies. RESULTS: One hundred and twenty-eight healthy participants (19-54 years of age) received pregabalin. Peak plasma concentrations (C max) were lower for CR than the respective pregabalin IR doses, and time to C max occurred later. When pregabalin CR was administered with food at midday or in the evening, total exposures [area under the plasma concentration-time curve from time zero extrapolated to infinite time (AUC∞)] were equivalent for pregabalin CR and IR formulations regardless of fat or caloric content. When pregabalin CR was administered with an 800-1,000 calorie medium-fat breakfast, AUC∞ was equivalent for pregabalin CR and IR. Bioequivalence criteria for comparison of pregabalin CR after a low- or medium-calorie breakfast relative to pregabalin IR were not met; however, bioavailability of the pregabalin CR vs. IR formulation was relatively high (75-86 %). When pregabalin CR was administered fasted, the AUC∞ was 70-78 % of the AUC∞ of pregabalin CR administered with food and bioequivalence criteria were not met. Additionally, the AUC∞ of the pregabalin CR formulation administered fasted was 62-69 % of that of pregabalin IR administered fasted and bioequivalence criteria were not met. Single-dose pregabalin CR and IR were well tolerated in all studies, with no serious or severe adverse events reported. CONCLUSION: Time of day of administration and the fat and caloric content of the accompanying meal had minimal overall effect on the pharmacokinetic properties and bioavailability of the pregabalin CR formulation.

Pregabalin controlled-release pharmacokinetics in healthy volunteers: analysis of four multiple-dose randomized clinical pharmacology studies.

BACKGROUND: Pregabalin (Lyrica(®)) is approved as an immediate-release (IR) formulation for administration twice (BID) or three times (TID) a day depending on indication. Once daily (QD) dosing may be appropriate for ease of clinical use and patient convenience. OBJECTIVES: The objectives of this analysis were: (1) to evaluate the pharmacokinetics of pregabalin controlled-release (CR) administered with food relative to the pregabalin IR formulation administered fasted; (2) to evaluate the pharmacokinetics of a two-tablet dose of pregabalin CR compared with the equivalent one-tablet dose of pregabalin CR; and (3) to determine the safety and tolerability of multiple-dose administration of pregabalin CR and IR. METHODS: The pharmacokinetic properties of pregabalin CR were determined in four phase I, open-label, multiple-dose crossover studies (18-24 participants/study). Pregabalin CR (82.5, 165, 330 or 660 mg/day) administered QD was compared with pregabalin IR (75, 150, 300 or 600 mg/day, respectively) administered either BID or TID. Blood samples were collected up to 24 h post-dose. Pharmacokinetic parameters were estimated from plasma concentration-time data using standard noncompartmental methods. Adverse events were monitored throughout all studies. RESULTS: Eight-four healthy participants (19-55 years of age) received pregabalin. For all pregabalin CR doses, total exposure was equivalent to the corresponding pregabalin IR dose. Relative bioavailability of pregabalin CR was 93-97 % of pregabalin IR, and bioequivalence criteria with respect to the 24-h steady-state exposure (area under the plasma concentration-time curve from 0 to 24 h [AUC24]) were met. Administration of a two-tablet dose of pregabalin CR was bioequivalent to one-tablet pregabalin CR. The relative bioavailability of two-tablet pregabalin CR was 97-102 % of one-tablet pregabalin CR, and bioequivalence criteria with respect to AUC24 and peak plasma concentrations were met. Pregabalin CR pharmacokinetic parameters were dose proportional following administration of 82.5-660 mg/day pregabalin CR. Pregabalin was well tolerated across studies, with no serious or severe adverse events. CONCLUSION: Total daily exposure with multiple-dose pregabalin CR is equivalent to the corresponding pregabalin IR dose.

The effect of mild and moderate hepatic impairment on the pharmacokinetics of tofacitinib, an orally active Janus kinase inhibitor.

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. We report here an evaluation of the pharmacokinetics of a single 10 mg dose of tofacitinib in healthy volunteers (n = 6) and subjects with mild (n = 6) or moderate (n = 6) hepatic impairment. Compared to healthy volunteers, tofacitinib area under the plasma concentration-time profile from time 0 to infinity (AUCinf ) and maximum observed concentration (Cmax ) in subjects with mild hepatic impairment were not altered. In subjects with moderate hepatic impairment, the geometric mean AUCinf and Cmax of tofacitinib were increased (90% confidence intervals of percentage increase) by approximately 65% (25%, 117%) and 49% (12%, 97%), respectively. A single dose of tofacitinib 10 mg resulted in two treatment-emergent adverse events (AE) in the mild hepatic impairment group, and one in the moderate hepatic impairment group; they were not considered related to study treatment. There were no deaths, serious AEs, discontinuations due to AEs, or dose reductions due to AEs. Data from this study were critical to deriving dose adjustments for subjects with hepatic impairment.

Bioequivalence assessment of a pregabalin capsule and oral solution in fasted healthy volunteers: a randomized, crossover study.

OBJECTIVE: To determine the oral bioavailability of a pregabalin capsule relative to a pregabalin solution. METHODS: This was an open-label, randomized, crossover study in 12 healthy volunteers. Pharmacokinetics were compared for a 100-mg capsule and a 100-mg capsule dissolved in water, administered fasted. RESULTS: Mean Cmax and AUC0-∞ for the capsule were within 2% of those for the solution (3.8 vs. 3.7 µg/ml and 26.7 vs. 27.0 µg×h/ml, respectively). The 90% confidence intervals for the ratios of Cmax and AUC0-∞ fell fully within 80 - 125%. CONCLUSIONS: A 100-mg pregabalin capsule is bioequivalent to a pregabalin solution (100-mg capsule dissolved in water).

Influence of mild and moderate hepatic impairment on axitinib pharmacokinetics.

OBJECTIVE: To evaluate the effects of hepatic impairment on the pharmacokinetics and safety of a single, oral axitinib dose in subjects with mild or moderate hepatic impairment. METHODS: In this phase I, open-label, parallel-group study, a total of 24 subjects with either normal hepatic function (n = 8) or with mild (n = 8) or moderate (n = 8) hepatic impairment were administered a single, oral dose of axitinib (5 mg). Blood samples were collected at intervals up to 144 h following dosing, and plasma pharmacokinetics and safety were assessed. Changes in axitinib plasma exposures in subjects with mild or moderate hepatic impairment were predicted using computer simulations and used to guide initial dosing in the clinical study. RESULTS: Axitinib exposure was similar in subjects with normal hepatic function and those with mild hepatic impairment, but approximately twofold higher in subjects with moderate hepatic impairment. Axitinib exposure weakly correlated with measures of hepatic function but was not affected by smoking status. Axitinib protein binding was similar in the three treatment groups. No significant treatment-related adverse events were reported. CONCLUSIONS: Compared with subjects with normal hepatic function, moderate hepatic impairment increased axitinib exposure, suggesting that the oral clearance of axitinib is altered in these subjects. In addition, these data indicate a possible need for a dose reduction in subjects who develop moderate or worse hepatic impairment during axitinib treatment. A single 5-mg dose of axitinib was well tolerated in subjects with mild or moderate hepatic impairment.

Clinical pharmacokinetics of pregabalin in healthy volunteers.

Pregabalin has shown clinical efficacy for treatment of neuropathic pain syndromes, partial seizures, and anxiety disorders. Five studies in healthy volunteers are performed to investigate single- and multiple-dose pharmacokinetics of pregabalin. Pregabalin is rapidly absorbed following oral administration, with peak plasma concentrations occurring between 0.7 and 1.3 hours. Pregabalin oral bioavailability is approximately 90% and is independent of dose and frequency of administration. Food reduces the rate of pregabalin absorption, resulting in lower and delayed maximum plasma concentrations, yet the extent of drug absorption is unaffected, suggesting that pregabalin may be administered without regard to meals. Pregabalin elimination half-life is approximately 6 hours and steady state is achieved within 1 to 2 days of repeated administration. Corrected for oral bioavailability, pregabalin plasma clearance is essentially equivalent to renal clearance, indicating that pregabalin undergoes negligible nonrenal elimination. Pregabalin demonstrates desirable, predictable pharmacokinetic properties that suggest ease of use. Because pregabalin is eliminated renally, renal function affects its pharmacokinetics.

Pregabalin drug interaction studies: lack of effect on the pharmacokinetics of carbamazepine, phenytoin, lamotrigine, and valproate in patients with partial epilepsy.

PURPOSE: Pregabalin (PGB) is an alpha2-delta ligand with demonstrated efficacy in epilepsy, neuropathic pain, and anxiety disorders. PGB is highly efficacious as adjunctive therapy in patients with refractory partial seizures. METHODS: Given its efficacy as adjunctive therapy, the potential for interaction of PGB with other antiepileptic drugs (AEDs) was assessed in patients with partial epilepsy in open-label, multiple-dose studies. Patients received PGB, 600 mg/day (200 mg q8h) for 7 days, in combination with their individualized maintenance monotherapy with valproate (VPA), phenytoin (PHT), lamotrigine (LTG), or carbamazepine (CBZ). RESULTS: Trough steady-state concentrations of CBZ (and its epoxide metabolite), PHT, LTG, and VPA were unaffected by concomitant PGB administration. Likewise, PGB steady-state pharmacokinetic parameter values were similar among patients receiving CBZ, PHT, LTG, or VPA and, in general, were similar to those observed historically in healthy subjects receiving PGB alone. The PGB-AED combinations were generally well tolerated. PGB may be added to VPA, LTG, PHT, or CBZ therapy without concern for pharmacokinetic drug-drug interactions.

Pharmacokinetics of pregabalin in subjects with various degrees of renal function.

The objectives of this study were to determine the single-dose pharmacokinetics of pregabalin in subjects with various degrees of renal function, determine the relationship between pregabalin clearance and estimated creatinine clearance (CLcr), and measure the effect of hemodialysis on plasma levels of pregabalin. Results form the basis of recommended pregabalin dosing regimens in patients with decreased renal function. Thirty-eight subjects were enrolled to ensure a wide range of renal function (CLcr < 30 mL/min, n = 8; 30-50, n = 5; 50-80, n = 7; and > 80, n = 6). Also enrolled were 12 subjects with renal impairment requiring hemodialysis. Each subject received 50 mg of pregabalin as two 25-mg capsules in this open-label, parallel-group study. Pregabalin concentrations were measured using previously validated liquid chromatographic methods. Pregabalin pharmacokinetic parameters were evaluated by established noncompartmental methods. Pregabalin was rapidly absorbed in all subjects. Total and renal pregabalin clearance were proportional (56% and 58%, respectively) to CLcr. As a result, area under the plasma concentration-time profile (AUC) and terminal elimination half-life (t1/2) values increased with decreasing renal function. Pregabalin dosage adjustment should be considered for patients with CLcr < 60 mL/min. A 50% reduction in pregabalin daily dose is recommended for patients with CLcr between 30 and 60 mL/min compared to those with CLcr > 60 mL/min. Daily doses should be further reduced by approximately 50% for each additional 50% decrease in CLcr. Pregabalin was highly cleared by hemodialysis. Supplemental pregabalin doses may be required for patients on chronic hemodialysis treatment after each hemodialysis treatment to maintain steady-state plasma pregabalin concentrations within desired ranges.