Pregabalin Population Pharmacokinetic and Exposure-Response Analyses for Focal Onset Seizures in Children (4-16 years) and Adults, to Support Dose Recommendations in Children.

Pregabalin is approved in multiple countries as adjunctive therapy for adult patients with focal onset seizures (FOS; previously termed partial onset seizures). This study used population pharmacokinetic (PK) and exposure-response (E-R) analyses from pooled pregabalin concentration and efficacy data to compare pregabalin exposure and E-R relationships in pediatric and adult patients with FOS, to support pediatric dosage recommendations. A one-compartment disposition model was used, with first-order absorption and body surface area-normalized creatinine clearance on clearance. Individual pregabalin average steady-state concentrations were predicted and used in an E-R analysis of efficacy. The E-R relationship of pregabalin was similar in pediatric (4-16 years) and adult patients with FOS after accounting for differences in baseline natural log-transformed 28-day seizure rate and placebo effect. Population PK simulations showed that children aged 4-16 years and weighing ≥ 30 kg required pregabalin 2.5-10 mg/kg/day to achieve similar pregabalin exposure at steady-state to adult patients receiving the approved doses of 150-600 mg/day. For children 4-16 years weighing < 30 kg, a higher pregabalin dose of 3.5-14 mg/kg/day was required to achieve equivalent exposure at steady-state. The results support the dosage guidance provided in the pregabalin prescribing label, whereby pediatric patients (4-16 years) weighing < 30 kg should receive a 40% higher pregabalin dose (per kg of body weight) than patients weighing ≥ 30 kg to achieve similar exposure. Our combined modeling approach may provide guidance for future extrapolation assessment from adult to pediatric patients.

Evaluation of composite responder outcomes of pain intensity and physical function in neuropathic pain clinical trials: an ACTTION individual patient data analysis.

Integrating information on physical function and pain intensity into a composite measure may provide a useful method for assessing treatment efficacy in clinical trials of chronic pain. Accordingly, we evaluated composite outcomes in trials of duloxetine, gabapentin, and pregabalin. Data on 2287 patients in 9 trials for painful diabetic peripheral neuropathy (DPN) and 1513 patients in 6 trials for postherpetic neuralgia (PHN) were analyzed. All trials assessed pain intensity on a 0 to 10 numeric rating scale and physical function with the 10-item subscale of the Short Form-36, ranging 0 to 100 with higher scores indicating better function. Correlation between change in pain intensity from baseline to posttreatment and change in physical function was small in DPN (ρ = -0.22; P < 0.001) and nonsignificant in PHN (ρ = -0.05; P = 0.08). Assay sensitivities of 10 composite outcomes were examined in a random subsample of patients enrolled in pregabalin trials for DPN and PHN. Of these, a responder outcome of ≥50% improvement in pain intensity, or a ≥20% improvement in pain intensity and ≥30% improvement in physical function was not only significantly associated with pregabalin vs placebo in the development cohorts for both pain conditions but also in the validation cohorts. Furthermore, this composite outcome was cross-validated in trials of gabapentin for PHN and duloxetine for DPN, and had slightly lower number needed to treat than a standard responder outcome of ≥50% reduction in pain intensity. In summary, this study identified a composite outcome of pain intensity and physical function that may improve the assay sensitivity of future neuropathic pain trials.

Population pharmacokinetics of tanezumab in phase 3 clinical trials for osteoarthritis pain.

AIMS: The aims were to 1) develop the pharmacokinetics model to describe and predict observed tanezumab concentrations over time, 2) test possible covariate parameter relationships that could influence clearance and distribution and 3) assess the impact of fixed dosing vs. a dosing regimen adjusted by body weight. METHODS: Individual concentration-time data were determined from 1608 patients in four phase 3 studies conducted to assess efficacy and safety of intravenous tanezumab. Patients received two or three intravenous doses (2.5, 5 or 10 mg) every 8 weeks. Blood samples for assessment of tanezumab PK were collected at baseline, 1 h post-dose and at weeks 4, 8, 16 and 24 (or early termination) in all studies. Blood samples were collected at week 32 in two studies. Plasma samples were analyzed using a sensitive, specific, validated enzyme-linked immunosorbent assay. RESULTS: A two compartment model with parallel linear and non-linear elimination processes adequately described the data. Population estimates for clearance (CL), central volume (V1 ), peripheral volume (V2 ), inter-compartmental clearance, maximum elimination capacity (VM) and concentration at half-maximum elimination capacity were 0.135 l day(-1) , 2.71 l, 1.98 l, 0.371 l day(-1) , 8.03 µg day(-1) and 27.7 ng ml(-1) , respectively. Inter-individual variability (IIV) was included on CL, V1 , V2 and VM. A mixture model accounted for the distribution of residual error. While gender, dose and creatinine clearance were significant covariates, only body weight as a covariate of CL, V1 and V2 significantly reduced IIV. CONCLUSIONS: The small increase in variability associated with fixed dosing is consistent with other monoclonal antibodies and does not change risk : benefit.

A population pharmacokinetic analysis of sildenafil citrate in patients with erectile dysfunction.

AIMS: To analyse the pharmacokinetics of sildenafil citrate in patients with erectile dysfunction in order to characterize covariate relationships and assist in the development of rational dosage strategies. METHODS: A population pharmacokinetic sampling strategy was incorporated into five phase III clinical study protocols. Overall, 2077 patients, 1335 of whom received sildenafil, were asked to take an additional dose of study drug before their scheduled clinic visits on four or five occasions throughout the study duration. A single plasma sample was obtained at random times postdose (range 1--7 h), and a total of 4582 samples were assayed (average 3.4 samples per individual). RESULTS: For the population average patient (age 58 years; aspartate transaminase [AST], 24 IU l(-1); weight, 87 kg; not receiving CYP3A4 potential inhibitors), typical values for sildenafil (mean +/- SE) were 58.5 +/- 1.4 l h(-1) for apparent clearance (CL/F), 310 +/- 6.92 l for volume of distribution (V/F), and 2.6 +/- 0.176 h(-1) for first-order absorption constant (ka). The value for ka is associated with meal consumption within 2 h predose, at all other times ka was equivalent to an instantaneous bolus administration. The interindividual variabilities were 29% for CL/F, 20% for V/F, and 210% for ka. Over a dose range of 25--100 mg sildenafil, the pharmacokinetics exhibited dose proportionality. There was evidence of nonproportionality (40% increase on average) in relative bioavailability with respect to the 200-mg dose (P<0.001) relative to the other doses. Age, AST concentration, and co-administration with CYP3A4 potential inhibitors significantly influenced CL/F of sildenafil (P<0.001, for each relationship). For age and AST, the extent of the linear relationships (extrapolated from population average values) included a 4% decrease in CL/F for every decade increase and a 6% decrease in CL/F for every 10-unit increase, respectively. Following co-administration of CYP3A4 potential inhibitors, a 14% decrease in CL/F was estimated. Only body weight was found to significantly (P<0.001) influence V/F (a 6% increase in V/F for every 10-kg increase). CONCLUSIONS: The pharmacokinetics of, and covariate influences on, sildenafil in patients with erectile dysfunction were shown to be consistent with those demonstrated in phase I volunteer studies.