<p>For prevention and treatment of thrombotic diseases with an anticoagulant drug it is important that an adequate dose is given to avoid occurrence or recurrence of thrombosis, without increasing the risk of bleeding and other adverse events to unacceptable levels. The aim of this thesis was to develop mathematical models that describe the dose-concentration (pharmacokinetic) and concentration-response (pharmacodynamic) relationships of direct thrombin inhibitors, in order to estimate optimal dosages for treatment and long-term secondary prevention of venous thromboembolism (VTE).</p><p>Population pharmacokinetic-pharmacodynamic models were developed, based on data from clinical investigations in healthy volunteers and patients receiving intravenous inogatran, subcutaneous melagatran and/or its oral prodrug ximelagatran. The benefit-risk profiles of different ximelagatran dosages were estimated using clinical utility functions. These functions were based on the probabilities and fatal consequences of thrombosis, bleeding and elevation of the hepatic enzyme alanine aminotransferase (ALAT).</p><p>The studies demonstrate that the pharmacokinetics of melagatran and ximelagatran were predictable and well correlated to renal function. The coagulation marker, activated partial thromboplastin time (APTT), increased non-linearly with increasing thrombin inhibitor plasma concentration. Overall, the systemic melagatran exposure (AUC) and APTT were similarly predictive of thrombosis and bleedings. The identified relationship between the risk of ALAT-elevation and melagatran AUC suggests that the incidence approaches a maximum at high exposures. The estimated clinical utility was favourable compared to placebo in the overall study population and in special subgroups of patients following fixed dosing of ximelagatran for long-term secondary prevention of VTE. Individualized dosing was predicted to add limited clinical benefit in this indication.</p><p>The models developed can be used to support the studied dosage and for selection of alternative dosing strategies that may improve the clinical outcome of ximelagatran treatment. In addition, the models may be extrapolated to aid the dose selection in clinical trials with other direct thrombin inhibitors.</p>

For prevention and treatment of thrombotic diseases with an anticoagulant drug it is important that an adequate dose is given to avoid occurrence or recurrence of thrombosis, without increasing the risk of bleeding and other adverse events to unacceptable levels. The aim of this thesis was to develop mathematical models that describe the dose-concentration (pharmacokinetic) and concentration-response (pharmacodynamic) relationships of direct thrombin inhibitors, in order to estimate optimal dosages for treatment and long-term secondary prevention of venous thromboembolism (VTE). Population pharmacokinetic-pharmacodynamic models were developed, based on data from clinical investigations in healthy volunteers and patients receiving intravenous inogatran, subcutaneous melagatran and/or its oral prodrug ximelagatran. The benefit-risk profiles of different ximelagatran dosages were estimated using clinical utility functions. These functions were based on the probabilities and fatal consequences of thrombosis, bleeding and elevation of the hepatic enzyme alanine aminotransferase (ALAT). The studies demonstrate that the pharmacokinetics of melagatran and ximelagatran were predictable and well correlated to renal function. The coagulation marker, activated partial thromboplastin time (APTT), increased non-linearly with increasing thrombin inhibitor plasma concentration. Overall, the systemic melagatran exposure (AUC) and APTT were similarly predictive of thrombosis and bleedings. The identified relationship between the risk of ALAT-elevation and melagatran AUC suggests that the incidence approaches a maximum at high exposures. The estimated clinical utility was favourable compared to placebo in the overall study population and in special subgroups of patients following fixed dosing of ximelagatran for long-term secondary prevention of VTE. Individualized dosing was predicted to add limited clinical benefit in this indication. The models developed can be used to support the studied dosage and for selection of alternative dosing strategies that may improve the clinical outcome of ximelagatran treatment. In addition, the models may be extrapolated to aid the dose selection in clinical trials with other direct thrombin inhibitors.

Metabolism is the sum of all chemical processes with the purpose to maintain life, as well as enable reproduction, in a living organism. Through the study of metabolism, increased understanding of pharmacological mechanisms and diseases can be achieved. This thesis describes several ways of doing so, including targeted analysis of selected metabolites and investigations of systematic metabolic differences between selected groups through pattern recognition. A method for exploring metabolic patterns in urine samples after intake of coffee or tea was developed. The methodology was later used with the aim to find biomarkers for prostate cancer and urinary bladder cancer. Furthermore, a fully automated quantitative method was developed for concentration measurements of the double prodrug ximelagatran and its metabolites in pig liver. The method was then used to study the roll of active transporters in pig liver cells. Moreover, a fundamental study was conducted to investigate how monitoring of small, doubly charged analytes can improve the limit of detection and precision in a quantitative method. The techniques used for the experiments were liquid separation coupled to electrospray mass spectrometry. Extra efforts were made to make the separation and the ionization as compatible as possible to each other for increased quality of the collected data.

Biliary excretion is an important elimination route for many drugs and metabolites. For such compounds, it is important to know the extent of excretion and drug exposure in the bile, e.g., for the risk assessment of drug interactions, liver toxicity and the effects of genetic variants. In this thesis, duodenal aspiration of bile was performed in healthy volunteers and complemented with experiments in an in vivo model in pigs to increase the understanding of the intestinal and hepatobiliary disposition of two direct thrombin inhibitors. The compounds investigated, ximelagatran and AZD0837, are both prodrugs that require bioactivation to exert their pharmacological effect. Upon co-administration with erythromycin and ketoconazole, respectively, altered plasma exposure to ximelagatran and AZD0837 and their respective metabolites has been observed. The main objective of this thesis was to characterize the biliary excretion of the compounds, and investigate whether this elimination route explains the observed drug-drug interactions. High plasma-to-bile AUC ratios were observed, in particular for ximelagatran, its active metabolite melagatran, and AR-H067637, the active metabolite of AZD0837. These high ratios indicate the involvement of active transporters in the biliary excretion of the compounds, which is important since transporters constitute possible sites for drug interactions. The effects of erythromycin and ketoconazole on the plasma exposure of the prodrugs and metabolites were confirmed in both the pig and the clinical studies. The changes seen in plasma for ximelagatran and its metabolites were partly explained by reduced biliary clearance. Inhibited CYP3A4 metabolism likely caused the elevated plasma levels of AZD0837, whereas reduced biliary clearance was seen for AR-H067637 suggesting an effect on its excretion into bile. In summary, the studies led to mechanistic insights in the hepatobiliary disposition of ximelagatran and AZD0837, and demonstrate the value of combined clinical and animal studies for the investigation of the biliary drug excretion.