AbstractsMedical & Health Science

Both primary pharmacokinetic (PK) parameters, volume of distribution (Vd) and clearance (CL), undergo considerable developmental changes in infancy and childhood, necessitating compensatory changes in dosing regimens if therapeutic effect without toxicity is to be reached and maintained. Neonates exhibit higher body water content and decreased plasma binding capacity compared to adults, producing increased Vd values for many drugs. Due to immaturity of glomerular function and low metabolic enzyme expression, CL tends to be significantly decreased in neonates. Both Vd and CL undergo simultaneous but independent maturation during development. Performing pediatric clinical trials is challenging due to ethical and practical constraints. Modeling and simulation approaches, such as population pharmacokinetic (POP-PK) and physiologically based pharmacokinetic (PBPK) modeling, are beneficial aids in planning and performing clinical studies in children. The aim of the literary review is to assess the developmental phenomena that cause pediatric pharmacokinetics to differ from adults, the clinical consequences arising from these differences, and present ways to apply POP-PK and PBPK models in pediatric drug research. In the experimental work, two modeling approaches for the prediction of pediatric pharmacokinetics are explored. First, the performance of the commercial PBPK software Simcyp in simulating a drug-drug interaction between cyclosporine A (CsA) and ketoconazole (KTZ) is assessed. Second, a method for in vitro-in vivo extrapolation (IVIVE) of CL in children is developed and evaluated. The aim is to assess the suitability of both modeling methods in pediatric drug research. Simcyp predicted the general age-related trends in the CsA CL and CsA-KTZ interaction well for the most part. However, the values of the simulated CL terms and magnitude of the simulated interaction were significantly under- and overpredicted, respectively. Due to limited clinical data, though, Simcyp performance could not be fully validated. The method developed here for IVIVE of pediatric CL values yielded successful predictions in most cases, with in vitro data from hepatocytes performing slightly better when compared to microsomal data. Success in extrapolations performed for adults correlated well with success in the pediatric extrapolations. Therefore, in drug development, the method developed in this work would be most useful after adult PK data is available, before the first pediatric clinical studies. Vastasyntyneellä monien lääkkeiden jakautumistilavuus on suurentunut kehon suhteellisesti suuremman vesipitoisuuden sekä plasman proteiinien pienemmän sitomiskapasiteetin vuoksi. Puhdistuma puolestaan on pienentynyt vastasyntyneellä kypsymättömän munuaistoiminnan sekä alhaisen maksaentsyymien ilmentymisen vuoksi. Jakautumistilavuus ja puhdistuma kehittyvät lapsuudessa samanaikaisesti ja toisistaan riippumatta. Lapsille annettavia lääkeannoksia ja antoväliä on sovitettava kehittyvä farmakokinetiikka huomioiden. Kliinisten lääketutkimusten…