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Pharmacology & Therapeutics Jan 2021Drug-drug interactions (DDI) and genomic variation (PG) can lead to dangerously high blood and tissue concentrations with some drugs but may be negligible with other...
How precise is quantitative prediction of pharmacokinetic effects due to drug-drug interactions and genotype from in vitro data? A comprehensive analysis on the example CYP2D6 and CYP2C19 substrates.
Drug-drug interactions (DDI) and genomic variation (PG) can lead to dangerously high blood and tissue concentrations with some drugs but may be negligible with other drugs. Using a quantitative metaanalysis, we analyzed on the example of CYP2D6 and CYP2C19 substrates, how well the effects of DDI and PG can be predicted by in vitro methods. In addition, we analyzed the quantitative effect of prototypic inhibitors of the two enzymes in relation to their genetic deficiency. More than 600 published studies were screened which compared either human pharmacokinetics with and without comedication, or which compared human pharmacokinetics of deficient with extensive metabolizers, or which assessed metabolism by in vitro approaches. With human liver microsomes, the in vitro to in vivo agreement of fractional clearances was reasonably high if loss of substrate was quantified in the in vitro assays performed with and without enzyme specific inhibitors. Also a generally very high correlation between the clinical pharmacokinetic effects of inherited deficiency and inhibition by drug-drug interactions could be demonstrated. Most cases of poor correlation were explained by the lack of CYP2D6 versus CYP2C19 specificity of fluoxetine or by a poor knowledge of the quantitative contribution of the metabolic pathways if metabolite formation was quantified in the in vitro assays. The good correspondence of the in vitro data with clinical DDI and clinical PG studies may be a good basis for future application of these methods in drug development and drug therapy.
Topics: Area Under Curve; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP2D6; Drug Interactions; Fluoxetine; Genotype; Humans; In Vitro Techniques; Models, Biological; Pharmacogenomic Variants; Pharmacokinetics; Substrate Specificity
PubMed: 32682785
DOI: 10.1016/j.pharmthera.2020.107629 -
Fertility and Sterility Dec 2020To investigate whether levothyroxine is associated with improved live birth and other benefits in women with thyroid autoimmunity. (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To investigate whether levothyroxine is associated with improved live birth and other benefits in women with thyroid autoimmunity.
DESIGN
Systematic review and meta-analysis.
SETTING
Not applicable.
PATIENT(S)
Women positive for thyroid peroxidase antibody.
INTERVENTION(S)
MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched without any language restrictions. Pooled effect sizes were calculated using random-effects models.
MAIN OUTCOME MEASURE(S)
The primary outcome was the incidence of live birth, miscarriage, preterm birth, clinical pregnancy, ectopic pregnancy, neonatal admission, and birth weight. The summary measures were reported as relative risk (RR) with 95% confidence interval.
RESULT(S)
Levothyroxine supplementation was not associated with an increased rate of live birth or a decreased risk of miscarriage. Results were similar in subgroup analyses of live birth by age, baseline thyrotropin, baseline thyroid peroxidase antibody, body mass index, and use of assisted conception. For live birth, the effect estimate lay within the futility boundary for RR of 20% and 15%, but at a 10% RR, the effect estimate lay between the futility boundary and the inferior boundary.
CONCLUSION(S)
High- to moderate-quality evidence demonstrated that the use of levothyroxine was not associated with improvements in clinical pregnancy outcomes among women positive for thyroid peroxidase antibody.
REGISTRATION NUMBER
PROSPERO CRD42019132976.
Topics: Adult; Autoantibodies; Autoantigens; Autoimmune Diseases; Biomarkers; Birth Weight; Female; Humans; Infant, Newborn; Iodide Peroxidase; Iron-Binding Proteins; Live Birth; Pregnancy; Pregnancy Complications; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors; Thyroid Diseases; Thyroxine
PubMed: 32912635
DOI: 10.1016/j.fertnstert.2020.06.034