Homoarginine is an endogenous amino acid whose levels are reduced in patients with renal, cardio- and cerebrovascular disease. Moreover, low homoarginine concentrations independently predict morbidity and mortality in these patients. Besides endogenous synthesis, homoarginine is also a constituent of the human diet. The objective of the present study was to analyze the kinetics of orally supplemented homoarginine in human plasma by means of a pharmacometric approach. We developed a pharmacometric model to evaluate different dosing regimens, especially the regimen of 125 mg once weekly, based on a previous clinical study (n = 20). The model was adapted to account for differences in baseline homoarginine plasma concentrations between healthy and diseased individuals. A novel dosing regimen of 25 mg once daily led to higher attainment of homoarginine reference concentrations using clinical trial simulations. With 25 mg/day, the trough concentration of only 6% of the older and 3.8% of the younger population was predicted to be below the target concentration of 2.0–4.1 µmol/L. In synopsis, the new dosing regimen recapitulates the kinetics of homoarginine in healthy individuals optimally.
Background Lassa fever is endemic in large parts of West Africa. The recommended antiviral treatment is ribavirin. Two treatment regimens are currently endorsed in Nigeria: the “McCormick regimen” based on a study published in 1986 and the “Irrua regimen” constituting a simplified schedule developed at the Irrua Specialist Teaching Hospital (ISTH), Nigeria. Evidence for the safety and efficacy of ribavirin in Lassa fever patients is poor and pharmacokinetic data for both regimens are lacking. Methods PCR-confirmed Lassa fever patients with mild to moderate disease severity were invited to participate in this prospective, observational pharmacokinetic study. Pharmacokinetics of ribavirin, clinical, virologic, and clinical laboratory parameters were assessed. Results Using a population pharmacokinetic approach, plasma concentrations of ribavirin were best described by a three-compartment model. Drug exposure was remarkably consistent between participants. Overall, drug clearance was 28.5% lower in female compared to male participants. Median (5th-95th percentile) time above IC50 was 37.3% (16.9%-73.1%), 16.7% (8.2%-58.5%) and 9.6% (4.9%-38.4%) on days 1, 7 and 8, respectively. Clinical laboratory parameters indicated reduction of cell damage and development of hemolytic anemia in the course of the treatment period. Conclusions This observational study characterizes the pharmacokinetics of ribavirin in the treatment of Lassa fever indicating consistent exposure across patients. Whereas the only short time interval of concentrations above the IC50 implies rather low antiviral efficacy in vivo, the prominent reduction of cell damage markers might point to indirect – potentially anti-inflammatory – effects of ribavirin. The role of ribavirin in the treatment of Lassa fever requires further scrutiny.
Ribavirin ist ein Breitspektrum-Virostatikum, das zur Therapie einer Reihe an schweren Virusinfektionen inkl. viral-hämorrhagischer Fieber (VHF) verwendet wird. Lassafieber ist ein VHF, das in weiten Teilen Westafrikas endemisch und für bis zu 300 000 Infektionen sowie 5000 Todesfälle pro Jahr verantwortlich ist. Hochdosisribavirin wird trotz eher schwacher Evidenz für die Therapie des Lassafiebers empfohlen und großflächig angewandt. In dieser Studie wurde die Pharmakokinetik der Therapie mit Hochdosisribavirin bei Lassafieberpatienten untersucht und so erste pharmakokinetische Daten für die Verwendung von Ribavirin bei VHF erhoben.
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