Prasarn Manitpisitkul

Pharmacokinetics and safety of adjunctive topiramate in infants (1–24 months) with refractory partial-onset seizures: A randomized, multicenter, open-label phase 1 study

Purpose:  To characterize the pharmacokinetics of adjunctive topiramate in infants (1–24 months) with refractory partial‐onset seizures (POS); also to evaluate safety and tolerability of topiramate in the dose range of 3–25 mg/kg/day.

Effect of canagliflozin on the pharmacokinetics of glyburide, metformin, and simvastatin in healthy participants

Drug–drug interactions between canagliflozin, a sodium glucose co‐transporter 2 inhibitor, and glyburide, metformin, and simvastatin were evaluated in three phase‐1 studies in healthy participants. In these open‐label, fixed sequence studies, participants received: Study 1‐glyburide 1.25 mg/day (Day 1), canagliflozin 200 mg/day (Days 4–8), canagliflozin with glyburide (Day 9); Study 2‐metformin 2,000 mg/day (Day 1), canagliflozin 300 mg/day (Days 4–7), metformin with canagliflozin (Day 8); Study 3‐simvastatin 40 mg/day (Day 1), canagliflozin 300 mg/day (Days 2–6), simvastatin with canagliflozin (Day 7). Pharmacokinetic parameters were assessed at prespecified intervals. Co‐administration of canagliflozin and glyburide did not affect the overall exposure (maximum plasma concentration [Cmax] and area under the plasma concentration–time curve [AUC]) of glyburide and its metabolites (4‐trans‐hydroxy‐glyburide and 3‐cis‐hydroxy‐glyburide). Canagliflozin did not affect the peak concentration of metformin; however, AUC increased by 20%. Though Cmax and AUC were slightly increased for simvastatin (9% and 12%) and simvastatin acid (26% and 18%) following coadministration with canagliflozin, compared with simvastatin administration alone; however, no effect on active 3‐hydroxy‐3‐methyl‐glutaryl‐CoA (HMG‐CoA) reductase inhibitory activity was observed. There were no serious adverse events or hypoglycemic episodes. No drug–drug interactions were observed between canagliflozin and glyburide, metformin, or simvastatin. All treatments were well‐tolerated in healthy participants.

Effect of food on the pharmacokinetics of canagliflozin, a sodium glucose co-transporter 2 inhibitor, and assessment of dose proportionality in healthy participants

Canagliflozin, an orally active inhibitor of sodium glucose co‐transporter 2, is approved for the treatment of type‐2 diabetes mellitus. The effect of food on the pharmacokinetics of 300 mg canagliflozin, and dose proportionality of 50, 100, and 300 mg canagliflozin, were evaluated, in two studies, in healthy participants. Study 1 used a randomized, 2‐way crossover design: canagliflozin 300 mg/day was administered under fasted (Period‐1) and fed (Period‐2) conditions or vice versa. Study 2 was a 3‐way crossover: participants were randomized to receive three single‐doses of canagliflozin (50, 100, and 300 mg), one in each period. In both studies, treatment periods were separated by washout intervals of 10–14 days, and pharmacokinetics assessed up to 72 hours postdose of each treatment period. No clinically relevant food effects on canagliflozin exposure parameters were observed: 90% confidence intervals (CIs) for the fed/fasted geometric mean ratios of AUC∞ (ratio: 100.51; 90% CI: 89.47–112.93) and Cmax (ratio: 108.09; 90% CI: 103.45–112.95) were entirely within bioequivalence limits (80–125%). Plasma canagliflozin exposures were dose‐proportional as the 90% CI of the slope of the regression line for dose‐normalized AUC∞ and Cmax fell entirely within the prespecified limits of −0.124 to 0.124. No clinically significant safety issues were noted, and canagliflozin was generally well‐tolerated.

Pharmacokinetics of topiramate in patients with renal impairment, end-stage renal disease undergoing hemodialysis, or hepatic impairment

PURPOSE Topiramate is primarily renally excreted. Chronic renal and hepatic impairment can affect the clearance of topiramate. Therefore, the objective was to establish dosage guidelines for topiramate in chronic renal impairment, end-stage renal disease (ESRD) undergoing hemodialysis, or chronic hepatic impairment patients. METHODS In 3 separate open-label, parallel group studies (n=5-7/group), in patients with mild-moderate and severe renal impairment (based on creatinine clearance), ESRD requiring hemodialysis, or moderate-severe hepatic impairment (based on Child-Pugh classification) and matching healthy participants, pharmacokinetics of a single oral 100mg topiramate was determined. RESULTS Compared with healthy controls, overall exposure (AUC0-∞) for topiramate was higher in mild-moderate (85%) and severe renal impairment (117%), consistent with significantly (p<0.05) lower apparent total body clearance (CL/F) and renal clearance (CLR), leading to longer elimination half-life. Both CLR and CL/F of topiramate correlated well with renal function. CL/F was comparable in ESRD and severe renal impairment. Half of usual starting and maintenance dose is recommended in moderate-severe renal impairment patients, and those with ESRD. Hemodialysis effectively removed plasma topiramate with mean dialysis clearance approximately 12-fold greater than CL/F (123.5 mL/min versus 10.8 mL/min). Compared with healthy matched, patients with moderate-severe hepatic impairment exhibited small increase (29%) in topiramate peak plasma concentrations and AUC0-∞ values, consistent with lower CL/F (26%). Topiramate was generally well tolerated. CONCLUSION Half of usual dose is recommended for moderate-severe renal impairment and ESRD. Supplemental dose may be required during hemodialysis. Dose adjustments might not be required in moderate-severe hepatic impairments; however, the small sample size limits generalization.

Pharmacokinetic interactions between topiramate and pioglitazone and metformin

OBJECTIVE To investigate potential drug-drug interactions between topiramate and metformin and pioglitazone at steady state. METHODS Two open-label studies were performed in healthy adult men and women. In Study 1, eligible participants were given metformin alone for 3 days (500 mg twice daily [BID]) followed by concomitant metformin and topiramate (titrated to 100mg BID) from days 4 to 10. In Study 2, eligible participants were randomly assigned to treatment with pioglitazone 30 mg once daily (QD) alone for 8 days followed by concomitant pioglitazone and topiramate (titrated to 96 mg BID) from days 9 to 22 (Group 1) or to topiramate (titrated to 96 mg BID) alone for 11 days followed by concomitant pioglitazone 30 mg QD and topiramate 96 mg BID from days 12 to 22 (Group 2). An analysis of variance was used to evaluate differences in pharmacokinetics with and without concomitant treatment; 90% confidence intervals (CI) for the ratio of the geometric least squares mean (LSM) estimates for maximum plasma concentration (Cmax), area under concentration-time curve for dosing interval (AUC12 or AUC24), and oral clearance (CL/F) with and without concomitant treatment were used to assess a drug interaction. RESULTS A comparison to historical data suggested a modest increase in topiramate oral clearance when given concomitantly with metformin. Coadministration with topiramate reduced metformin oral clearance at steady state, resulting in a modest increase in systemic metformin exposure. Geometric LSM ratios and 90% CI for metformin CL/F and AUC12 were 80% (75%, 85%) and 125% (117%, 134%), respectively. Pioglitazone had no effect on topiramate pharmacokinetics at steady state. Concomitant topiramate resulted in decreased systemic exposure to pioglitazone and its active metabolites, with geometric LSM ratios and 90% CI for AUC24 of 85.0% (75.7%, 95.6%) for pioglitazone, 40.5% (36.8%, 44.6%) for M-III, and 83.8% (76.1%, 91.2%) for M-IV, respectively. This effect appeared more pronounced in women than in men. Coadministration of topiramate with metformin or pioglitazone was generally well tolerated by healthy participants in these studies. CONCLUSIONS A modest increase in metformin exposure and decrease in topiramate exposure was observed at steady state following coadministration of metformin 500 mg BID and topiramate 100mg BID. The clinical significance of the observed interaction is unclear but is not likely to require a dose adjustment of either agent. Pioglitazone 30 mg QD did not affect the pharmacokinetics of topiramate at steady state, while coadministration of topiramate 96 mg BID with pioglitazone decreased steady-state systemic exposure to pioglitazone, M-III, and M-IV. While the clinical consequence of this interaction is unknown, careful attention should be given to the routine monitoring for adequate glycemic control of patients receiving this concomitant therapy. Concomitant administration of topiramate with metformin or pioglitazone was generally well tolerated and no new safety concerns were observed.

A randomized study to evaluate the analgesic efficacy of a single dose of the TRPV1 antagonist mavatrep in patients with osteoarthritis

Abstract Background/Aims Transient receptor potential vanilloid type 1 (TRPV1) receptor antagonists have been evaluated in clinical studies for their analgesic effects. Mavatrep, a potent, selective, competitive TRPV1 receptor antagonist has demonstrated pharmacodynamic effects consistent with target engagement at the TRPV1 receptor in a previous single-dose clinical study. The current study was conducted to evaluate the analgesic effects of a single dose of mavatrep. Methods In this randomized, placebo- and active-controlled, 3-way crossover, phase 1b study, patients with painful knee osteoarthritis were treated with a single-dose of 50 mg mavatrep, 500 mg naproxen twice-daily, and placebo. Patients were randomized to 1 of 6 treatment sequences. Each treatment sequence included three treatment periods of 7 days duration with a 7 day washout between each treatment period. The primary efficacy evaluation was pain reduction measured by the 4-h postdose sum of pain intensity difference (SPID) based on the 11-point (0-10) Numerical Rating Scale (NRS) for pain after stair-climbing (PASC). The secondary efficacy evaluations included 11-point (0-10) NRS pain scores entered into the Actiwatch between clinic visits, the Western Ontario and McMaster Universities Arthritis Index subscales (WOMAC) questionnaire, and use of rescue medication. Safety and tolerability of single oral dose mavatrep were also assessed. Results Of 33 patients randomized, 32 completed the study. A statistically significantly (p<0.1) greater reduction in PASC was observed for mavatrep versus placebo (4-h SPID least square mean [LSM] [SE] difference: 1.5 [0.53]; p = 0.005 and 2-h LSM [SE] difference of PID: 0.7 [0.30]; p = 0.029). The mean average daily current pain NRS scores were lower in the mavatrep and naproxen treatment arm than in the placebo arm (mavatrep: 7 day mean [SD], 3.72 [1.851]; naproxen: 7 day mean [SD], 3.49 [1.544]; placebo: 7 day mean [SD], 4.9 [1.413]). Mavatrep showed statistically significant improvements as compared with placebo on the WOMAC subscales (pain on days 2 [p = 0.049] and 7 [p = 0.041], stiffness on day 7 [p = 0.075]), and function on day 7 [p = 0.077]). The same pattern of improvement was evident for naproxen versus placebo. The mean (SD) number of rescue medication tablets taken during the 7-day treatment period was 4.2 (6.49) for mavatrep treatment, 2.8 (5.42) for naproxen, and 6.3 (8.25) for placebo treatment. All patients that received mavatrep reported at least 1 treatment emergent adverse event (TEAE). Feeling cold (79%), thermohypoesthesia (61%), dysgeusia (58%), paraesthesia (36%), and feeling hot (15%) were the most common TEAEs in the mavatrep group. Total 9% patients receiving mavatrep experienced minor thermal burns. No deaths or serious AEs or discontinuations due to AEs occurred. Conclusion Overall, mavatrep was associated with a significant reduction in pain, stiffness, and physical function when compared with placebo in patients with knee osteoarthritis. Mavatrep’s safety profile was consistent with its mechanism of action as a TRPV1 antagonist. Implications Further studies are required to evaluate whether lower multiple doses of mavatrep can produce analgesic efficacy while minimizing adverse events, as well as the potential for improved patient counselling techniques to reduce the minor thermal burns related to decreased heat perception. Trial Registration 2009-010961-21 (EudraCT Number).

Pharmacokinetic interactions between topiramate and diltiazem, hydrochlorothiazide, or propranolol

Drug–drug interactions between topiramate and diltiazem, hydrochlorothiazide, or propranolol were evaluated along with safety/tolerability in three open‐label studies. Healthy participants (aged 18–45 years) received topiramate 75 mg every 12 hours (q12h) and diltiazem 240 mg/day (study 1); topiramate 96 mg q12h and hydrochlorothiazide 25 mg/day (study 2); topiramate 100 mg q12h and propranolol 40–80 mg q12h (study 3). The pharmacokinetic parameters for topiramate, diltiazem (and active metabolites, desacetyldiltiazem [DEA], N‐demethyl diltiazem [DEM]), hydrochlorothiazide, and propranolol (and its active metabolite) were assessed at steady state. Results showed no effect of diltiazem on topiramate pharmacokinetics. However, a modest reduction in systemic exposures of diltiazem and DEA (10–27%) occurred during coadministration with topiramate. Systemic exposure of DEM was unaffected. Furthermore, oral and renal clearance of topiramate decreased (22–30%) significantly (P < 0.05) during coadministration with hydrochlorothiazide, while systemic exposure increased by 27–29%. Topiramate had no effect on hydrochlorothiazide pharmacokinetics. The results demonstrated lack of pharmacokinetic interaction between topiramate and propranolol. Overall, no new safety concerns emerged when topiramate was coadministered with diltiazem, hydrochlorothiazide, or propranolol.

Phase 0 study of the inhibition of cholesteryl ester transfer protein activity by JNJ-28545595 in plasma from normolipidemic and dyslipidemic humans.

OBJECTIVE To assess and validate the application of a non-radioactive assay for cholesteryl ester transfer protein (CETP) activity in clinical samples. DESIGN AND METHODS In this Phase 0 study, CETP activity was measured following addition of the CETP inhibitor JNJ-28545595 to plasma samples from normolipidemic and three subgroups of dyslipidemic subjects with differing lipid profiles. RESULTS CETP activity was elevated in plasma samples from dyslipidemic subjects compared to normolipidemic subjects. Increased triglyceride levels correlated with decreased CETP inhibition. The assay was found to have good analytical precision and high throughput potential as required for clinical trial sample analysis. CONCLUSIONS The results demonstrate that pharmacological inhibition of CETP is affected by the dyslipidemic nature of plasma samples. In addition, since the optimal degree of CETP inhibition for maximal cardiovascular benefit in patients is not known, this assay may be used to help define optimal dosing of CETP inhibitors.

Bioavailability and Pharmacokinetics of TRPV1 Antagonist Mavatrep (JNJ‐39439335) Tablet and Capsule Formulations in Healthy Men: Two Open‐Label, Crossover, Single‐Dose Phase 1 Studies

To improve room temperature stability and oral bioavailability of mavatrep (JNJ‐39439335, a transient receptor potential vanilloid subtype‐1 antagonist), various formulations were initially developed and evaluated in 2 phase 1 open‐label, randomized, 3‐way crossover studies in healthy participants. Study 1 evaluated 2 new overencapsulated tablet formulations (formulations B and C) relative to an overencapsulated early tablet formulation (formulation A), using mavatrep HCl salt form. Because these tablets were still not room‐temperature stable, in study 2: two free‐base solid dispersion amorphous formulations (formulations D and E) were evaluated relative to the best encapsulated formulation from study 1 (formulation C) and also food effect. Both studies had screening (∼4 weeks), treatment (study 1: n = 18, 6‐sequenced; formulations B and C [2 × 25 mg] versus A [2 × 25 mg]; study 2, part 1: n = 24, formulations D and E [2 × 12.5 mg] versus C [1 × 25 mg]; study 2, part 2: n = 16, best formulation from part 1 fed versus fasted, 2 × 12.5 mg) with a 21‐day washout period and a follow‐up. Mavatrep exhibited consistent pharmacokinetics across formulations. Following rapid absorption (median tmax, 1.5–6.5 hours), plasma concentrations declined multiexponentially (mean t1/2, 67–104 hours). The new encapsulated tablet formulation (formulation C, capsule filler: poloxamer 407) was the best formulation (Cmax and AUC values 2‐3‐fold > than the other 2) from study 1. Using this as a reference in study 2, part 1, only small (<20%) differences in mean Cmax and AUC were observed between the 3 formulations (C, D, and E). Formulation E (gelatin capsule with amorphous solid dispersion [12.5 mg free base], hydroxypropyl methylcellulose, vitamin E polyethylene glycol succinate, silicified microcrystalline cellulose, magnesium stearate, colloidal silicon dioxide) showed improved room‐temperature stability and provided the best overall bioavailability with small variability. Small effects of a high‐fat meal on oral bioavailability were observed for formulation E, but were not clinically meaningful. Mavatrep safety profiles were similar across formulations and under fasted and fed conditions. No new safety concerns were reported.

Pharmacokinetics and Safety of Mavatrep (JNJ-39439335), a TRPV1 Antagonist in Healthy Japanese and Caucasian Men: A Double-Blind, Randomized, Placebo-Controlled, Sequential-Group Phase 1 Study

This single‐center, double‐blind, placebo‐controlled, sequential‐group phase 1 study evaluated the safety, tolerability, and pharmacokinetics (PK) of mavatrep (JNJ‐39439335), a transient receptor potential vanilloid 1 antagonist, in healthy Japanese and caucasian subjects. In part 1, a single‐ascending‐dose study, 50 subjects (25 each healthy Japanese and caucasians) were enrolled and received a single oral dose of 10, 25, or 50 mg mavatrep. Caucasian subjects were matched to Japanese subjects with respect to age (±5 years) and body mass index (±5 kg/m2). In part 2, a multiple‐ascending‐dose study, 36 Japanese subjects were enrolled and received once‐daily oral doses of 10, 25, or 50 mg of mavatrep for 21 days. The single‐dose PK of mavatrep and its metabolites was similar in the Japanese and caucasian subjects after adjustment of body weight. Following multiple dosing in Japanese subjects, a steady‐state condition was reached in approximately 14 days. M2 and M3 are major circulating metabolites with mean exposure > 10% of mavatrep. Nonrenal clearance was the major route of elimination for mavatrep, M2, and M3. Mavatrep exhibited a long half‐life, ranging from 68 to 101 and 82–130 hours for Japanese and caucasian subjects, respectively. After single and multiple dosing, mavatrep was well tolerated. The most common adverse events observed were thermohypoesthesia, feeling cold, chills, and feeling hot. Mavatrep and its metabolites exhibited similar PK profiles after single ascending doses in healthy Japanese and caucasian men.