Browsing by Author "Simonsson, USH"

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    Open Access
    Optimization of 1st-line antituberculosis dosing regimens using a population pharmacokinetic approach: food effects, drug combinations and pharmacological effects
    (2014) Zvada, Simbarashe Peter; McIlleron, Helen; Simonsson, USH
    The aim of this thesis was to evaluate optimal doses of 1st-line antituberculosis dosing regimens using a population pharmacokinetic approach, quantify food effects, drug combinations and pharmacological effects. The population pharmacokinetics of rifampicin, isoniazid and pyrazinamide in 76 children with tuberculosis were described using a population pharmacokinetic approach, and then Monte Carlo simulation were performed to evaluate adequacy of newly recommended weight band based doses in World Health Organisation (WHO) guidelines. Food effect (breakfast) was evaluated on rifapentine pharmacokinetic data in 35 healthy male volunteers. Effect of co-administered intermittent rifapentine on the pharmacokinetics of moxifloxacin was evaluated in 28 patients with pulmonary tuberculosis, who participated in a multicenter controlled clinical trial evaluating high dose rifapentine in combination with moxifloxacin. The moxifloxacin pharmacokinetic model, together with a previously published ofloxacin pharmacokinetic model, was used to evaluate the efficacy between moxifloxacin and ofloxacin. Furthermore, pharmacokinetic summary variables of rifapentine and moxifloxacin were evaluated as predictors of treatment outcome. Simulations based on the final models suggested that with the new guidelines, and utilizing available paediatric fixed dose combinations, children will receive adequate rifampicin exposures when compared to adults, but with a larger degree of variability. However, pyrazinamide and isoniazid exposures in many children will be lower than in adults. For food effect, all meals compared with the fasting state, high fat meal had the greatest effect on rifapentine oral bioavailability, increasing it by 86%; bulky low-fat, bulky-high-fat, and chicken soup resulted in 33%, 46%, and 49% increases in rifapentine oral bioavailability, respectively. Similar trends were observed for the metabolite 25-desacetyl rifapentine. For drug-resistant tuberculosis, using a target ratio of ≥100 for multidrug-resistant strains (without resistance to injectable agents or fluoroquinolones), the cumulative fraction of response (CFR) was 88% for moxifloxacin and only 43% for ofloxacin. The higher dose of 800 mg moxifloxacin was needed to achieve a CFR target of ≥90%. In terms of drug-interaction, rifapentine increased the clearance of moxifloxacin by 8% during antituberculosis treatment compared to that after treatment completion without rifapentine. Also, the effect moxifloxacin and rifapentine pharmacokinetics indices on outcome treatment outcome support that combined effect of longer treatment duration and higher rifapentine exposures are associated with better treatment response. In summary, the newer WHO doses for children may give lower pyrazinamide and isoniazid exposures in many children than in adults. Meals have a substantial impact on rifapentine exposure. Rifapentine did not result in a clinically significant change in moxifloxacin exposure. Moxifloxacin is more efficacious than ofloxacin in the treatment of MDR-TB. The combined effect of longer treatment duration, higher rifapentine exposures are associated with better treatment outcome, but could not differentiate which major factor needed for favourable outcome.
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    Open Access
    Population pharmacokinetics of lopinavir and ritonavir in combination with rifampicin-based antitubercular treatment in HIV-infected children
    (Springer, 2010) Zhang, C; Denti, P; Simonsson, USH; Maartens, Gary; Karlsson, MO; McIlleron, H
    Children with HIV associated tuberculosis often require co-formulated lopinavir/ritonavir (LPV/RTV)-based antiretroviral treatment with rifampicin-based antitubercular treatment (ATT). Rifampicin (RIF), a potent inducer of drug-metabolizing systems, profoundly reduces the bioavailability of LPV. The aims of this study were to develop an integrated population pharmacokinetic (PK) model describing LPV and RTV PK in children with and without concomitant ATT using two different dosing approaches and to estimate doses of LPV/RTV achieving target exposures during ATT in young children.