Christine Alvey

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.

Pregabalin Drug Interaction Studies: Lack of Effect on the Pharmacokinetics of Carbamazepine, Phenytoin, Lamotrigine, and Valproate in Patients with Partial Epilepsy

Summary:  Purpose: Pregabalin (PGB) is an α2‐δ ligand with demonstrated efficacy in epilepsy, neuropathic pain, and anxiety disorders. PGB is highly efficacious as adjunctive therapy in patients with refractory partial seizures.

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.

Safety and pharmacology of a single intravenous dose of ponezumab in subjects with mild-to-moderate Alzheimer disease: a phase I, randomized, placebo-controlled, double-blind, dose-escalation study.

ObjectivesPonezumab is a humanized antiamyloid beta (A&bgr;) monoclonal antibody designed to treat Alzheimer disease (AD). MethodsThis randomized, double-blind, single-dose-escalation study evaluated the safety, pharmacokinetics, and pharmacodynamics of 0.1, 0.3, 1, 3, and 10 mg/kg ponezumab (n = 4, 4, 4, 6, and 8, respectively) versus placebo (n = 11) after a 2-hour intravenous infusion in subjects with mild-to-moderate AD. Cerebrospinal fluid (CSF) samples were obtained from the 1- and 10-mg/kg groups at baseline and at day 29. The subjects were followed for 1 year. ResultsAll subjects completed the trial. Ponezumab was well tolerated with no drug-attributed serious adverse events. The most common adverse events were upper respiratory tract infection, headache, and back pain, all mild to moderate. One subject (10 mg/kg) experienced a mild hypersensitivity reaction. Another subject (0.1 mg/kg) demonstrated slight enlargement of a preexisting midbrain lesion. Electrocardiography and laboratory values (including CSF) were unremarkable. No evidence of new microhemorrhage, vasogenic edema, or meningoencephalitis was noted. Plasma maximum observed concentration increased approximately dose proportionally, and the area under the plasma concentration-time profile from time zero extrapolated to infinite time (AUCinf) increased slightly more than dose proportionally. Mean terminal half-life was approximately 6 weeks. Two subjects (10 mg/kg) had measurable CSF ponezumab concentrations (~0.5% of plasma values) at day 29. Plasma A&bgr;1-x and A&bgr;1-40 increased dose dependently, and mean CSF A&bgr;1-x increased 38% from baseline with 10 mg/kg (P = 0.002 vs placebo). ConclusionsA 2-hour infusion of 0.1 to 10 mg/kg ponezumab was well tolerated in subjects with mild-to-moderate AD. Plasma pharmacokinetic profile was approximately linear. Plasma A&bgr; increased with dose, and CSF A&bgr; increased at the highest dose, suggesting that intravenous ponezumab alters central A&bgr; levels.

Safety and pharmacology of ponezumab (PF-04360365) after a single 10-minute intravenous infusion in subjects with mild to moderate Alzheimer disease.

ObjectivePonezumab (PF-04360365) is a humanized anti–amyloid beta (A&bgr;) monoclonal antibody designed for treatment of Alzheimer disease (AD). A single 2-hour intravenous infusion of 0.1 to 10 mg/kg was previously shown to be safe and well tolerated in subjects with mild to moderate AD, with measurable effects on plasma and cerebrospinal fluid A&bgr;. This phase I, dose-escalation, open-label study evaluated the safety, pharmacokinetics, and pharmacodynamics of a single 10-minute intravenous infusion. MethodsSubjects with mild to moderate AD received ponezumab 1 mg/kg (n = 3), 3 mg/kg (n = 3), 5 mg/kg (n = 4), or 10 mg/kg (n = 5). They were followed up as outpatients for 6 months. ResultsAll subjects completed the trial. Ponezumab was safe and well tolerated with no deaths, withdrawals, or drug-related moderate, severe, or serious adverse events. Mild drug-related adverse events included headache (3 patients) and lethargy and hypoesthesia (both in 1 patient). No infusion reactions, clinically meaningful laboratory abnormalities, vital sign changes, electrocardiographic changes, or antidrug antibodies were detected. There was no evidence of brain microhemorrhage, vasogenic edema, encephalitis, or other imaging abnormality. Cognitive function showed no treatment-related trends. Ponezumab displayed approximately dose-proportional increases in plasma exposure. Steady-state volume of distribution was 113 to 172 mL/kg, clearance was 2.7 to 3.0 mL/d/kg, and terminal half-life was 35 to 52 days. Plasma maximum observed concentration and the area under the plasma concentration-time profile from time 0 extrapolated to infinite time of A&bgr;1-x and A&bgr;1-40 increased dose-dependently. ConclusionsAdministration of ponezumab as a 10-minute infusion was safe and well tolerated and produced effects on plasma A&bgr; species comparable with a 2-hour infusion. Shorter infusions may provide more flexibility, comfort, and convenience for patients and caregivers.

Effect of Gemfibrozil and Fenofibrate on the Pharmacokinetics of Atorvastatin

Coadministration of statins and fibrates is beneficial in some patients by allowing simultaneous reduction of triglycerides and low‐density lipoprotein cholesterol alongside elevation of high‐density lipoprotein cholesterol. However, the potential for drug interactions must be taken into consideration. Gemfibrozil increases systemic exposure to various different statins, whereas similar effects are not observed with fenofibrate, suggesting it may be a more appropriate choice for coadministration with statins. Gemfibrozil is reported to cause a moderate increase in the area under the curve (AUC) of atorvastatin, but the effect of fenofibrate on atorvastatin pharmacokinetics has not been described. This study compared the effects of multiple‐dose administration of gemfibrozil and fenofibrate on the single‐dose pharmacokinetics of atorvastatin. Gemfibro zil coadministration led to significant increases in the AUC of atorvastatin, 2‐hydroxyatorvastatin, 2‐hydroxyatorvastatin lactone, and 4‐hydroxyatorvastatin lactone. In contrast, fenofibrate administration did not lead to clinically meaningful changes in the AUC for atorvastatin, atorvastatin lactone, 2‐hydroxyatorvastatin, or 2‐hydroxyatorvastatin lactone. The absence of a significant pharmacokinetic interaction between fenofibrate and atorvastatin is consistent with recent results showing no difference in safety profile between atorvastatin as monotherapy or in combination with fenofibric acid. Together, these data suggest that atorvastatin‐fenofibrate combination therapy is unlikely to pose a risk to patients.

Lack of effect of tofacitinib (CP-690,550) on the pharmacokinetics of the CYP3A4 substrate midazolam in healthy volunteers: confirmation of in vitro data

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Tofacitinib (CP-690,550) is a novel, oral Janus kinase inhibitor being investigated as a targeted immunomodulator and disease-modifying therapy in rheumatoid arthritis. • Non-renal elimination accounts for 70% of the total clearance of tofacitinib and the metabolism is primarily mediated by cytochrome P450 (CYP) 3A4. • This study was required to determine the effect of tofacitinib on the in vivo pharmacokinetics of a sensitive CYP3A4 substrate. WHAT THIS STUDY ADDS • The pharmacokinetics of midazolam, a sensitive CYP3A4 substrate, are not altered when co-administered with tofacitinib in healthy subjects. • Tofacitinib is unlikely to affect the clearance of drugs metabolized by CYP enzymes. • There is no need for dose adjustments of CYP substrates when co-administered with tofacitinib. AIMS To investigate inhibitive and inductive effects of tofacitinib (CP-690,550), a Janus kinase inhibitor, on CYP3A4 function via in vitro and in vivo studies. METHODS In vitro experiments were conducted to assess the inhibition and induction potential of tofacitinib for major drug metabolizing enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4). A phase 1, randomized, open-label, two-way crossover study (NCT00902460) was conducted to confirm the lack of inhibitive/inductive effect on a sensitive CYP3A4 substrate, midazolam, in healthy subjects. Midazolam pharmacokinetics were assessed over 24 h following single dose 2 mg administration prior to administering tofacitinib and after twice daily dosing of tofacitinib 30 mg for 6 days. The primary endpoint was midazolam area under the concentration-time profile, from time 0 to infinity (AUC(0,∞)). RESULTS In vitro studies demonstrated low potential for CYP inhibition (IC(50) estimates tofacitinib > 30 µm), CYP3A4 mRNA induction (observed at tofacitinib concentrations ≥ 25 µm) and no effect on enzymatic activity of CYP substrates. In the human study, AUC(0,∞) adjusted geometric mean ratio for midazolam plus tofacitinib to midazolam alone was 103.97% [90% confidence interval (CI) 95.57, 113.12], wholly within the pre-specified acceptance region (80, 125). The 90% CI for the ratio of adjusted geometric means of maximum plasma concentration (C(max) ) (95.98, 108.87) was also wholly within this acceptance region. CONCLUSIONS These data confirm a lack of an inhibitive or inductive effect of tofacitinib on CYP3A activity in humans and, in conjunction with in vitro data, support the conclusion that tofacitinib is unlikely to influence the CYP enzyme system as a whole.

Effects of fesoterodine on the pharmacokinetics and pharmacodynamics of warfarin in healthy volunteers

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Drug-drug interactions with warfarin are common with potentially harmful consequences. Preclinical in vitro studies suggest that fesoterodine or 5-hydroxymethyl tolterodine are not likely to affect warfarin metabolism, but a lack of interaction has not been demonstrated in a clinical study. WHAT THIS STUDY ADDS This study shows that the pharmacokinetics and pharmacodynamics of warfarin 25 mg in healthy adults are unaffected by fesoterodine 8 mg, and that co-administration of warfarin 25 mg and fesoterodine 8 mg is safe and well tolerated. AIMS To confirm the lack of an interaction of fesoterodine 8 mg with warfarin pharmacokinetics and pharmacodynamics in healthy adults. METHODS In this open-label, two-treatment, crossover study, subjects (n= 14) aged 20-41 years with normal prothrombin time (PT) and International Normalized Ratio (INR) were randomized to receive a single dose of warfarin 25 mg alone in one period and fesoterodine 8 mg once daily on days 1-9 with a single dose of warfarin 25 mg co-administered on day 3 in the other period. There was a 10-day washout between treatments. Pharmacokinetic endpoints were area under the plasma concentration-time curve from time 0 to infinity (AUC(0,∞)), maximum plasma concentration (C(max)), AUC from time 0 to the time of the last quantifiable concentration (AUC(0,last)), time to C(max) (t(max) ), and half-life (t(1/2)) for S- and R-warfarin. Pharmacodynamic endpoints were area under the INR-time curve (AUC(INR) ), maximum INR (INR(max)), area under the PT-time curve (AUC(PT)) and maximum PT (PT(max)). RESULTS Across all pharmacokinetic and pharmacodynamic comparisons, the point estimates of treatment ratio (warfarin co-administered with fesoterodine vs. warfarin alone) were 92-100%. The 90% confidence intervals for the ratios of the adjusted geometric means were contained within (80%, 125%). There were no clinically relevant changes in laboratory tests, vital signs or ECG recordings. CONCLUSIONS The pharmacokinetics and pharmacodynamics of warfarin 25 mg in healthy adults are unaffected by fesoterodine 8 mg. Concomitant administration of fesoterodine and warfarin was well tolerated.

Effects of the moderate CYP3A4 inhibitor, fluconazole, on the pharmacokinetics of fesoterodine in healthy subjects

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Available data suggest that fesoterodine dosage should not exceed 4 mg once daily when taken concomitantly with potent CYP3A4 inhibitors, such as ketoconazole. Currently, no information is available on whether dose adjustment is necessary when fesoterodine is administered with a moderate CYP3A4 inhibitor. WHAT THIS STUDY ADDS This study shows that adjustment of fesoterodine dose is not warranted when co-administered with a moderate CYP3A4 inhibitor. AIMS To assess the effects of fluconazole, a moderate CYP3A4 inhibitor, on the pharmacokinetics (PK) and safety/tolerability of fesoterodine. METHODS In this open-label, randomized, two-way crossover study, 28 healthy subjects (18-55 years) received single doses of fesoterodine 8 mg alone or with fluconazole 200 mg. PK endpoints, including the area under the plasma concentration-time curve from 0 to infinity (AUC(0,∞)), maximum plasma concentration (C(max) ), time to C(max) (t(max) ), and half-life (t(1/2) ), were assessed for 5-hydroxymethyl tolterodine (5-HMT), the active moiety of fesoterodine. RESULTS Concomitant administration of fesoterodine with fluconazole increased AUC(0,∞) and C(max) of 5-HMT by approximately 27% and 19%, respectively, with corresponding 90% confidence intervals of (18%, 36%) and (11%, 28%). There was no apparent effect of fluconazole on 5-HMT t(max) or t(½) . Fesoterodine was generally well tolerated regardless of fluconazole co-administration, with no reports of death, serious adverse events (AEs) or severe AEs. Following co-administration of fesoterodine with fluconazole, 13 subjects (48%) experienced a total of 40 AEs; following administration of fesoterodine alone, six subjects (22%) experienced a total of 19 AEs. The majority of AEs were of mild intensity. There were no clinically significant changes in laboratory or physical examination parameters. CONCLUSION Fesoterodine 8 mg single dose was well tolerated when administered alone or with fluconazole. Based on the observed increase in 5-HMT exposures being within the inherent variability of 5-HMT pharmacokinetics, adjustment of fesoterodine dose is not warranted when co-administered with a moderate CYP3A4 inhibitor provided they are not also inhibitors of transporters.

Drug Interactions with Clinafloxacin

ABSTRACT Many fluoroquinolone antibiotics are inhibitors of cytochrome P450 enzyme systems and may produce potentially important drug interactions when administered with other drugs. Studies were conducted to determine the effect of clinafloxacin on the pharmacokinetics of theophylline, caffeine, warfarin, and phenytoin, as well as the effect of phenytoin on the pharmacokinetics of clinafloxacin. Concomitant administration of 200 or 400 mg of clinafloxacin reduces mean theophylline clearance by approximately 50 and 70%, respectively, and reduces mean caffeine clearance by 84%. (R)-Warfarin concentrations in plasma during clinafloxacin administration are 32% higher and (S)-warfarin concentrations do not change during clinafloxacin treatment. An observed late pharmacodynamic effect was most likely due to gut flora changes. Phenytoin has no effect on clinafloxacin pharmacokinetics, while phenytoin clearance is 15% lower during clinafloxacin administration.