Oxaliplatin is an anticancer drug widely used in cancer chemotherapy. This thesis evaluates whether a specific dose-banding scheme for oxaliplatin could replace the individual dosing method that is currently used in the oxaliplatin administration. Dose-banding was introduced into UK clinical practice in 2001, as it reduces delays in patients receiving their treatment and, through quality control and end-product testing, safeguards the infusion quality and patient safety. A range of studies were included in this thesis: an extended stability study on oxaliplatin infusions using a sequential temperature cycling design; studies on oxalate, a potential degradation product and metabolite of oxaliplatin which has been linked to oxaliplatin neurotoxicity and the development of an ex vivo pharmacokinetic (PK) simulation model to compare the effect of different oxaliplatin dosing methods on its therapeutic outcomes. The shelf-life of oxaliplatin infusions over a concentration range of 0.2 mg/mL – 0.7 mg/mL is extended to 84 days when stored at 2 – 8℃ plus a further 7 days after being left at room temperature (25℃) for 24 hours. This ensures the unused oxaliplatin infusions are safe to be re-issued to patients, which could reduce drug wastage. The oxalate study suggests that the dose-limiting neurotoxicity of oxaliplatin is unlikely to be directly related to the oxalate produced from oxaliplatin degradation in infusions or from the non-enzymic transformation of oxaliplatin in vivo because the oxalate levels from these routes are minor compared to the endogenous level. The safety and efficacy of dose-banding schemes was demonstrated by comparing the simulated PK characteristics gained from the ex vivo model. Dose-banding with the +10% maximum deviation was selected as the most promising dosing scheme for oxaliplatin. Finally, recommendations are made concerning the introduction of oxaliplatin dose-banding scheme into clinical practice, and on the benefits of harmonised dose-banding schemes.

Paracetamol är ett vanligt använt läkemedel med analgesisk och antipyretisk effekt. Läkemedlet finns tillgängligt i ett flertal beredningsformer och doseringsstyrkor för användning både receptfritt och i sjukhusvården. Syftet med detta projekt var att undersöka påverkan av alternativ, off-label, dosering av paracetamol i pediatrisk vård, med hjälp av fysiologiskt baserad farmakokinetisk (PBPK) modellering. Modellen utvecklades först för en vuxen population genom integrering av in vitro, in vivo och in silico data för paracetamol. Efter detta extrapolerades concentrationskurvor till en pediatrisk population med hjälp av ontogeni-information. Modellen validerades i både vuxna och barn, och var tillförlitlig för både peroral och intravenös dosering. Efter valideringen utfördes simuleringar för nio olika åldersgrupper baserat på rekommenderade doseringsprotokoll i Sverige. Simuleringarna visade att perorala tablettdoseringen var jämförbar med formulering i lösningsform, med snarlika maximumkoncentrationer och area-under-kurvan (AUC) för exponering. Hastigheten av magtömning influerade maximumkoncentrationer men inte AUC. Ytterligare testades modellens förmåga att prediktera plasmakoncentrationer i blodet efter överdosering med paracetamol. Dessa prediktioner fungerade bättre när läkemedelsmetaboliserande enzymer lämnades oförändrade, eller ökade något i aktivitet. Slutligen, den utvecklade PBPK-modellen kan användas för att säkert undersöka olika doseringsprotokoll och för design av pediatriska kliniska studier. / Paracetamol, a widely used analgesic and antipyretic drug, can be found in various formulations and doses for both home and hospital use. The aim of this study was to investigate the impact of off-label dosing of paracetamol in pediatric clinical practice using physiologically based pharmacokinetic (PBPK) modeling. The model was initially developed for adults by integrating relevant in vitro, in vivo and in silico data of paracetamol, after which the model was extrapolated for pediatrics by adding ontogeny information. The model was successfully validated in both adult and pediatric populations, and it showed accuracy for both oral and intravenous administration routes. After validation, simulations were conducted across nine different age groups following the recommended doses in Sweden. These simulations showed that tablet dose is comparable to solution dosing, resulting in nearly identical maximum concentrations and area under the curve (AUC) values. Furthermore, it was observed that gastric emptying time, which reflects the fed state of individuals, significantly influences the maximum concentration, with longer gastric emptying times resulting in lower and delayed peak concentrations. However, the gastric emptying time had no effect on the AUC values. Lastly, the model’s performance on overdose data was evaluated, and it turned out that it performs better when liver enzymes were not affected, or they were only slightly elevated. Finally, the developed PBPK model can be further used for safe and effective way of exploring dose banding and designing clinical trials in pediatrics.