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Τετάρτη 27 Ιουλίου 2022

Pharmacokinetics of ribavirin in the treatment of Lassa fever: An observational clinical study at the Irrua Specialist Teaching Hospital, Edo State, Nigeria

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Abstract
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.
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Association of histo‐blood group antigens and predisposition to gastrointestinal diseases

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Abstract

Infectious gastroenteritis is a common illness afflicting people worldwide. The two most common etiological agents of viral gastroenteritis, rotaviruses and noroviruses are known to recognise histo-blood group antigens (HBGAs) as attachment receptors. ABO, Lewis, and secretor HBGAs are distributed abundantly on mucosal epithelia, cell membranes, and also secreted in biological fluids, such as saliva, intestinal content, milk and blood. HBGAs are fucosylated glycans that have been implicated in the attachment of some enteric pathogens such as bacteria, parasites, and viruses. Single nucleotide polymorphisms in the genes encoding ABO (H), fucosyltransferase gene FUT2 (Secretor/Se), FUT3 (Lewis/Le) have been associated to changes in enzyme expression and HBGAs production. The highly polymorphic HBGAs among different populations and races influence genotype specific susceptibility or resistance to enteric pathogens and its epidemiolog y, and vaccination seroconversion. Therefore, there is an urgent need to conduct population-based investigations to understand predisposition to enteric infections and gastrointestinal diseases. This review focuses on the relationship between HBGAs and predisposition to common human gastrointestinal illnesses caused by viral, bacterial, and parasitic agents.

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Pharmacokinetic and pharmacodynamic simulation for the quantitative risk assessment of linezolid‐associated thrombocytopenia

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Pharmacokinetic and pharmacodynamic simulation for the quantitative risk assessment of linezolid-associated thrombocytopenia

Utility of safety target achievement rate based on PK/PD simulation for predicting linezolid-induced thrombocytopenia-stratified on the duration of linezolid therapy.


Abstract

What Is Known and Objective

Linezolid (LZD) may cause thrombocytopenia, which can result in discontinuation of treatment. In this study, the blood LZD trough concentration was estimated based on population pharmacokinetic (PK) parameters derived from two previously published models in the Japanese population to determine the rate of achieving the target trough value when the risk of thrombocytopenia is low and to clarify its relationship with the onset of thrombocytopenia.

Methods

This study included adult patients hospitalized at Shimane University Hospital, who received LZD treatment for at least 4 days from January 2010 to December 2017. Patients whose platelet count fell below 70% before LZD administration were categorized as the thrombocytopenic group. Patient PK parameters were calculated based on the population PK models described by Matsumoto et al. and Sasaki et al., and these parameters were designated A and B, respectively. Based on these parameters, the rate of achieving an LZD trough concentration of less than 8 μg/ml, which is the safety target achievement rate, was calculated using a random simulation for each patient. We further analysed the association between the incidence of thrombocytopenia and patient factors, including safety target achievement rate, through univariate, multivariate, and receiver operating characteristic (ROC) analyses.

Results and Discussion

Patients (n = 77) aged 72 ± 11 years and weighing 56.7 ± 10.9 kg, with a creatinine clearance (CLcr) of 60.5 ± 47.2 ml/min and a cirrhosis prevalence of 9.1%, were analysed. All patients received LZD at a dose of 600 mg twice daily for a total of 10.9 ± 8.9 days. Univariate analyses revealed significant differences (p < 0.05) in the duration of LZD therapy, serum creatinine, creatinine clearance, LZD clearance, and the safety target achievement rate for parameters A and B between the thrombocytopenic and non-thrombocytopenic groups. A multivariate analysis of these factors stratified with the cutoff values obtained by ROC analysis revealed that the duration of LZD therapy and the safety target achievement rates for parameters A and B were significant factors (odds ratios for duration of LZD therapy: 7.436 [95% confidence interval (CI): 1.918–28.831] and 4.712 [95% CI: 1.567–14.163]; odds ratio for safe ty target achievement rate: 0.060 [95% CI: 0.016–0.232] and 0.167 [95% CI: 0.056–0.498] for parameters A and B, respectively). When the safety target achievement rates for patients treated with LZD were compared between the thrombocytopenic and non-thrombocytopenic groups, the safety target achievement rate was higher in the non-thrombocytopenic group in both the patients treated with LZD for less than 10 days and those for 10 days or more.

Therefore, the safety target achievement rate estimated by the PK/PD simulation may represent to be an important index for risk assessment of LZD-induced thrombocytopenia.

What Is New and Conclusion

The risk of LZD-induced thrombocytopenia, which increased with the duration of LZD therapy, may be predicted using the safety target achievement rate obtained by the blood concentration simulation.

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A homozygous loss-of-function variant in BICD2 is associated with lissencephaly and cerebellar hypoplasia

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