Population pharmacokinetics of pregabalin in healthy subjects and patients with chronic pain or partial seizures

Abstract

SUMMARYPurpose: Pregabalin, a high-affinity ligand for a2d subunits of voltage-gated calcium channels, is a novel pharmacotherapy for chronic pain, partial seizures, and other disorders. The present study investigated the population pharmacokinetics of pregabalin following single and multiple doses in healthy volunteers and patient populations. Methods: Using nonlinear mixed-effect modeling, 5,583 plasma pregabalin concentration-time samples from 1,723 subjects were analyzed: 2,868 samples from healthy volunteers or subjects with renal impairment (n = 123), 1,513 from patients with partial seizures (n = 626), and 1,202 from patients with chronic pain (n = 974). A one-compartment model with first-order elimination and absorption processes and absorption lag time was used.Key Findings: This pharmacostatistical model showed that: (1) pregabalin oral clearance (CL/F) was directly proportional to creatinine clearance (CLcr), but was independent of gender, race, age, female hormonal status, daily dose, and dosing regimen; (2) apparent volume of distribution was dependent on body weight and gender; (3) absorption rate was decreased when given with food; and (4) coadministration with marketed antiepileptic drugs (AEDs) had no significant effect on pregabalin CL/F. Significance: Pregabalin CL/F is related to CLcr, and this relationship is similar among healthy volunteers and patients with either partial seizures or chronic pain disorders. The only factor having a clinically significant influence on steady-state plasma pregabalin concentrations is renal function.

Comparison of oral absorption models for pregabalin: usefulness of transit compartment model

“…As illustrated in Figure 4, the individual predicted CL/F in the final model increased with CLCR without showing any saturation or breakpoint-like pattern around the CLCR 107 mL/min, which may have resulted from the relatively smaller number and homogeneity of the subjects in our study. The population CL/F of pregabalin reported previously was 4.96 L/h6 or 4.94 L/h7 in individuals with a CLCR of 107 mL/min and an IBW of 62 kg. In a typical individual with the same CLCR, the CL/F was predicted to be 5.89 L/h by our transit compartment model.…”

“…The population CL/F of pregabalin in the reports by Bockbrader et al6 and Shoji et al7 proportionally increased with CLCR up to a breakpoint of 107 mL/min (0.0464 or 0.0462× CLCR as mL/min) and remained unchanged beyond this point. However, such a breakpoint was not found in data from our healthy subjects.…”

“…Pregabalin is rapidly absorbed in the fasting state, with peak plasma concentrations occurring within 1 h. Food reduces the absorption rate, resulting in lowered and delayed maximum plasma concentration without a clinically significant effect on the extent (bioavailability) 5. A few studies on the population PK of pregabalin have been conducted;6–8 these studies commonly employed a one-compartment model with first-order absorption and elimination only without mentioning any attempt to find a better model. However, in these studies, a common trend to underestimate pregabalin concentrations around the time of maximum plasma concentration (T max ) was observed, which suggests the possibility of an inappropriate choice of absorption model (first-order absorption).…”

Pregabalin-induced first degree atrioventricular block in a young patient treated for pain from extrapulmonary tuberculosis

“…Firstly, pregabalin renal clearance is not different in Blacks compared to Caucasians or Hispanic [14]. Secondly, no differences in the therapeutic effects of the drug due to races have been reported.…”

Therapeutic Drug Monitoring of Classical and Newer Anticonvulsants

“…The oral clearance of pregabalin is proportional to creatinine clearance and is not altered by variables including sex, race, age, co-administration of other AEDs, or dosing schemes [99]. Drug interaction studies showed no significant changes in pharmacokinetics in those with partial epilepsy in combination therapy with carbamazepine, phenytoin, lamotrigine or valproate [100].…”