Studies of the pharmacokinetics (PK) and cognitive effects of antiepileptic drugs (AEDs) in the elderly populations remain limited. Optimal dosing of these drugs in the elderly patients requires the characterization of both inter and intraindividual variability in drug disposition and cognitive responses to AEDs. The aims of the current dissertation were to characterize the PK of carbamazepine (CBZ) and gabapentin (GBP), AEDs that are widely prescribed in the elderly population, in community-dwelling and nursing home older patients, respectively, and to conduct a quantitative assessment of covariates that influence the PK parameters of these drugs. We further quantified the effect of TPM, an AED with a unique cognitive signature affecting language use in a subset of patients, on adverse cognitive effects in healthy volunteers. The long-term goal of the latter study is to set the foundation for understanding the drug-induced cognitive impairment in the elderly populations.
The concentration-time and exposure-response data were analyzed by means of nonlinear mixed effects modeling in the NONMEM software. The population PK model of total and unbound CBZ in community-dwelling elderly patient with epilepsy found age to have no effect on the clearance (CL), volume of distribution or protein binding of CBZ. This model estimated a significant effect of race on the clearance of CBZ, where Caucasians had an average of 30% higher CL than African Americans. On the other hand, the PK characteristics of GBP in a frailer population of nursing home elderly patients were different from both community-dwelling patients and younger adults. We found the CL of GBP in a nursing home resident with a normal renal function (5.78 L/hr) to be slightly less than that of a community-dwelling elderly patient (8.5 L/hr) of comparable renal function. Furthermore, a dose-dependent bioavailability of GBP in nursing home older residents was demonstrated, and the extent of absorption was half saturated at a much lower dose (~480 mg) than in younger adults (~1100 mg). Model-based simulations suggested a substantial increase in systemic exposure with administration of high total daily dose (≥600 mg) as smaller doses of GBP given more often due to the increase in oral bioavailability. Population pharmacokinetic-pharmacodynamic (PK-PD) models were developed and quantified the effect of TPM exposure on the word-level verbal fluency performance in healthy volunteers. Studies in healthy volunteers enabled us to characterize the effect of TPM on generative fluency as measured by the controlled oral word association (COWA) test while excluding other confounders. We found the performance on COWA to decline in an exponential manner with increased TPM concentration, and that the ratio of COWA scores to baseline decreased by a factor of 0.85, on average, with each mg/L increase in TPM concentration. In addition, the PK-PD model enabled us to quantify and account for the significant practice effect (estimated to be 12% improvement in the COWA scores after the 3rd time the test was administered on drug-free sessions) in modeling the exposure-response profile. The estimated effect of TPM in our study was based on a narrow range of observed concentrations (0.05 – 3 mg/L) and low single oral and intravenous infusion dose (100 mg). As a result, we recommended future studies to administer a wider range of TPM doses to enable the characterization of the dose-response relationship. In conclusions, the results from the PK studies presented in this dissertation found that the elderly population is a heterogeneous group with respect to the PK of AEDs. Thus, extrapolation of results between different age groups within the elderly population may not be valid. Furthermore, the PK-PD analyses of cognitive effects of TPM in healthy volunteers successfully established quantitative models to predict cognitive performance at a particular level of TPM exposure and will be beneficial in generating hypotheses, research design and interpretation of PK-PD findings from future studies in the elderly population.
University of Minnesota Ph.D. dissertation. November 2012. Major: Experimental & clinical pharmacology. Advisors: Dr. Angela K. Birnbaum, Dr. Jatinder K. Lamba. 1 computer file (PDF); xiii, 128 pages, appendix p. 116-128.
Fathi Sawi Ahmed, Ghada.
Pharmacometric analyses of anti-epileptic drugs in elderly patients: applications to carbamazepine, gabapentin, and topiramate.
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