A Note on Pharmacokinetics Modelling of Theophylline Concentration Data on Patients with Respiratory Diseases

Abstract

Pharmacokinetics which describes the time course of drug absorption, distribution, metabolism, and excretion in the body is critical in formulating drug therapy. Nonlinear Mixed Effects (NLME) models are popularly used in many longitudinal studies, including human immunodeficiency viral dynamics, pharmacokinetic analyses, and studies of growth and decay.This work aimed to develop efficient NLME models for analyzing Theophylline concentration data within the pharmacokinetics framework. The data consisted of Theophylline concentration (mg/L) measurements of 12 asthmatic patients who were treated with oral Theophylline. The serum concentrations were measured at 11 times per subject over 25 hours periods. Hence, a total of 132 observations were obtained. Six different pharmacokinetics models were fitted in a step-wise manner to these data within the framework of NLME techniques. The best of these models that yielded the most efficient estimates of the physiological factors such as absorption rate ( ), elimination rate ( ), and clearance ( ) in the patients was determined using suitable model selection criteria. The results showed that the clearance and absorption rate have mixed effects with estimated values of = 0.0397 and = 1.54203 (for fixed effects) while the effect of the elimination rate in all the patients is fixed with the estimated value of =0.0860. Also, the low estimated standard deviations of the random effects components of (0.1699) and (0.6384)over the entire samples is a clear evidence that the fitted model was quite consistent and efficient.Results from this study would further serve as useful guides to clinicians and drug developers in the proper formulation and administration of Theophylline therapy on patients suffering from respiratory diseases.Keywords: Pharmacokinetics; theophylline concentration; nonlinear mixed effects model; compartmental model ÖZET Vücutta zamanla meydana gelen ilaç emilimi, dağılımı, metabolizması ve boşaltımını tanımlayan farmakokinetikler, ilaç terapi formüllerinde çok önemlidir. Doğrusal olmayan karışık etki (DOKE) modelleri, büyüme ve çürüme çalışmaları, farmakokinetik analizler ve insan immün yetmezliği viral dinamiklerini kapsayan birçok longitudinal çalışmada popüler olarak kullanılmaktadır. Bu çalışmada farmakokinetik yapı için teofilin konsantrasyon verisi analiz edilerek etkili DOKE modelleri geliştirmek amaçlanmaktadır. Veri seti, ağızdan teofilin ile tedavi edilen 12 astım hastasının teofilin konsantrasyon ölçümlerini içermektedir. Serum konsantrasyonları, 25 saatlik periyotlarla her hastadan 11 kez ölçülmüştür. Dolayısıyla 132 gözlem elde edilmiştir. DOKE teknikleri çerçevesinde bu veri seti için altı farklı farmakokinetik model aşamalı olarak tahmin edilmiştir. Hastalarda emilim hızı ( ), eleme hızı ( ) ve aralık ( ) gibi fizyolojik faktörlerin en etkili tahminini sağlayan en iyi modeller uygun model seçim kriteri kullanılarak belirlenmiştir. Sonuçlar, eleme hızının tüm hastalarda = 0.0860 tahmin değeri ile sabit olmasına rağmen, aralık ve emilim hız...

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