Browsing by Author "Wiesner, Lubbe Joachim"

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    Open Access
    Population pharmacokinetic modelling for dose optimization of esomeprazole to treat early-onset preeclampsia
    (2020) Semere, Gebreyesus Manna; Wiesner, Lubbe Joachim
    Rationale Esomeprazole is a proton pump inhibitor with preclinical efficacy data showing it lowers concentrations of soluble fms like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sEng), pathognomonic biomarkers identified in preeclampsia. A randomized controlled trial, Preeclampsia Intervention with Esomeprazole (PIE) trial, was conducted in South African women diagnosed with early-onset preeclampsia to investigate efficacy, but it found no change in clinical outcome or biomarker concentrations. It was hypothesized that the 40 mg daily oral dose was not enough to achieve therapeutic exposure. This study investigated the pharmacokinetics of esomeprazole in patients with early- onset preeclampsia with the aim to optimize the dose for future clinical trials. Methods Pharmacokinetic data from ten pregnant patients with early-onset preeclampsia from the PIE trial, median (range) age 30 (21-43) years, weight 98.8 (56-126) kg, and gestational age 29 (26- 31) weeks, were included for model development. In addition, pharmacokinetic data from non- pregnant healthy volunteers consisted of a pooled dataset of 26 male and female subjects, median (range) age of 21 (18-27) years and weight 69 (54-89) kg, who received 40 mg esomeprazole daily. Analysis of the pharmacokinetic data in pregnant patients was performed using nonlinear mixed-effects modelling with allometric scaling on clearance (CL) and volume of distribution (Vd). Metabolite to parent area under the time-concentration curve (AUCsulf/AUCeso and AUChyd/AUCeso) ratios were compared between pregnant and non-pregnant to assess metabolic changes in pregnancy. Simulations were performed with the model to determine the nonlinear increase in AUC with higher doses and with repeated dosing in the pregnant patients. Simulation results were compared with the preclinical target unbound concentration (0.917 mg/L) and preclinical target unbound AUC0-24 (9.29 mg·h/L). Results A one compartment pharmacokinetic model with first-order elimination and transit compartment absorption best described the data. Model estimated apparent CL and apparent Vd (95% CI) were 19.2 (14.2-26) L/h and 44.2 (29.9-56.6) L, respectively. Median AUCsulf/AUCeso (IQR) for pregnant patients, 2.00 (1.35-2.61) , was significantly higher than that for non-pregnant subjects on day1, 0.700 (0.636-1.00) , and day5, 1.18 (0.981- 1.58) . Median AUChyd/AUCeso (IQR) for pregnant patients, 0.0543 (0.0500-0.0914) , was not significantly different from that of non-pregnant subjects on day5, 0.0777 (0.0569-0.108) but lower than that of non-pregnant subjects on day1, 0.188 (0.156- 0.227). Simulation results showed that predicted steady state unbound Cmax is between 0.0949 and 0.398 mg/L while the predicted unbound AUC0-24 in pregnant patients with the highest dose of esomeprazole used clinically, i.e.120 mg BID, is between 0.696 and 2.92 mg·h/L. Discussion/Conclusion Model estimated CL/F and Vd/F are higher than values previously reported by other population pharmacokinetic models. AUCm/AUCp comparisons showed that esomeprazole metabolism in pregnancy appears to have shifted to the CYP3A4 pathway. This means that the nonlinear AUC increase expected with dose escalation and with repeated dosing are not as significant as in nonpregnant. Simulations indicate that pregnant patients are unlikely to achieve the target concentration and exposure with the highest dose of esomeprazole registered. Further research is necessary to determine the target site of action of esomeprazole in preeclampsia, and the pharmacokinetic metric that correlates with efficacy.
  • Thumbnail Image
    Item
    Open Access
    The characterization of pharmacokinetic properties and evaluation of in vitro drug combination efficacies of novel antimalarial compounds
    (2020) Laing, Lizahn; Wiesner, Lubbe Joachim; Gibhard, Liezl
    Relief of the global malaria burden relies on the management and application of effective therapies. Unfortunately, the continuous development of resistance to therapies by the deadliest parasite strain, Plasmodium falciparum, has made the treatment and control of malaria much more difficult. Derivatives of the Chinese peroxidic antimalarial drug artemisinin primarily used in first-line combination therapy for treatment of P. falciparum malaria have proved to be highly effective. However, their use also is now compromised by the development of resistance by the parasite to the artemisinin derivative in the drug combination. This event emphasizes the need for ongoing development of new and effective drug combinations. This research aimed to identify efficacious combinations selected from a group of compounds known to induce oxidative stress by redox cycling combined with an artemisinin, which as an oxidant drug also induces oxidative stress but is unable to undergo redox cycling. Combination of the artemisinin with a redox-active compound is expected to both enhance and maintain oxidative stress within the parasite's proliferative environment. These combinations should be used together with a third drug with a completely different mode of action, such as a quinolone. Selected amino artemisinins and redox active phenothiazines, phenoxazines, thiosemicarbazones, and quinolone derivatives were screened for antimalarial activity and mammalian toxicity. These were found to be potently active (11 μM) to Chinese Hamster ovarian (CHO) cells. The compounds are thus highly selective for P. falciparum, as revealed by the selectivity indices (SI) of >270. The in vitro absorption, distribution, metabolism, and elimination (ADME) properties of the compounds were also determined through the application of specific assays. In vivo pharmacokinetic (PK) profiling was also carried out by intravenous and oral administration of the individual compounds to healthy C57BL/6 mice. Biological samples were analysed via liquid chromatography-tandem mass spectrometry (LC-MS/MS) bioanalytical methods, which were validated according to the fit-for purpose recommendations by the FDA. Evaluation of the in vitro and in vivo profiles thereby facilitated the identification of suitable combination candidates. The phenoxazine and phenothiazine derivatives were identified as the best potential redox partners and were each investigated in combination with the amino-artemisinin artemisone through fixed ratio isobole analysis. A substantial synergistic interaction was observed. Overall, the investigation enabled the identification of drug combinations that are potently active in vitro. This synergistic interaction strongly supports the redox cycling rationale for identifying new antimalarial therapies and further suggests that such combinations in chemotherapy may delay the onset of resistance to the new agents. The results strongly encourage further investigation of the in vivo pharmacokinetic and pharmacodynamic (PK/PD) relationships of these combinations in the humanized murine model of P. falciparum