Apart from new anti-tuberculosis drug development, another approach for tuberculosis (TB) treatment optimization is to derive maximum benefit from current agents. However, the dosage of current ...anti-TB drug regimens has never been optimized according to the exposure-effect relationships of each drug. The objective of this article is to review the latest pharmacokinetic, pharmacodynamic, experimental, and clinical data concerning the use of higher doses of first-line anti-TB drugs to improve the efficacy of pulmonary tuberculosis treatment. Exposure-effect relationships have been described for all first-line anti-TB agents. There is convincing evidence that patients would benefit from higher rifamycin exposure. This could be achieved by using higher daily doses of rifampin, or more frequent dosing of rifapentine. The dose-dependent activity of pyrazinamide observed in hollow-fiber and animal models suggests that higher doses of pyrazimamide might be more efficacious, but the tolerability of such higher doses needs to be investigated in humans. It is likely that higher doses of ethambutol would be associated with higher antibacterial effect, but the dose-related ocular toxicity of the drug precludes such practice. For isoniazid, dose individualization is required to optimize patient care. The use of higher than standard doses of isoniazid in fast acetylators should result in greater early bactericidal activity. To conclude, the use of higher doses for some of the firstline anti-TB agents has definite potential for shortening or improving TB treatment.
Chronic kidney disease (CKD) may alter drug renal elimination but is also known for interacting with hepatic metabolism via multiple uremic components. However, few global models, considering the ...five major cytochromes, have been published, and none specifically address the decrease in cytochrome P450 (CYP450) activity. The aim of our study was to estimate the possibility of quantifying residual cytochrome activity as a function of filtration rate, according to the data available in the literature.
For each drug in the DDI-predictor database, we collected available pharmacokinetic data comparing drug exposition in the healthy patient and in various stages of CKD, before building a model capable of predicting the variation of exposure according to the degree of renal damage. We followed an In vivo Mechanistic Static Model (IMSM) approach, previously validated for predicting change in liver clearance. We estimated the remaining fraction parameters at glomerular filtration rate (GFR) = 0 and the alpha value of GFR to 50% impairment for the 5 major cytochromes using a non-linear constrained regression using Matlab software.
Thirty-one compounds had usable pharmacokinetic data, with 51 AUC ratios between healthy and renal impaired patients. The remaining CYP3A4 activity was estimated to be 0.4 when CYP2D6, 2C9, 2C19 and 1A2 activity was estimated to be 0.43; 1; 0.73 and 0.7, respectively. The alpha value was estimated to be at 6.62; 25; 9.8; 1.38 and 11.04 for each cytochrome. In comparison with published data, all estimates but one were correctly predicted in the range of 0.5-2.
Our approach was able to describe the impact of CKD on metabolic elimination. Modelling this process makes it possible to anticipate changes in clearance and drug exposure in CKD patients, with the advantage of greater simplicity than approaches based on physiologically-based pharmacokinetic modelling. However, a precise estimation of the impact of renal failure is not possible with an IMSM approach due to the large variability of the published data, and thus should rely on specific pharmacokinetic modelling for narrow therapeutic margin drugs.
The pharmacokinetics of ceftolozane-tazobactam (TOL-TAZ) and ceftazidime-avibactam (CEF-AVI) is influenced by renal function. Application of recommended dosages in patients with renal impairment ...requires the use of fractions of the full dose, as only one dosage is available for both antibiotics. The objective of this study was to evaluate the adequacy of alternative dosage regimens based on the full dose. We performed pharmacokinetic/pharmacodynamic (PK/PD) simulations of recommended and alternative dosage regimens in patients with various degrees of renal impairment by using the Pmetrics program. Alternative regimens included longer dosage interval and prolonged infusions of the full dose for both drugs. Probabilities of target attainment (PTA) were assessed considering PK/PD targets defined for cephalosporins and beta-lactamase inhibitors as well as MIC breakpoints. The risk of overexposure was also assessed. Results showed that alternative dosage regimens based on a full dose of TOL-TAZ and CEF-AVI administered every 12 or 24 h were associated with PTA similar to that of recommended dosages, especially when administered as prolonged infusion. The alternative dosage regimens were not associated with overexposure in most cases. In addition, those regimens could reduce dosing errors, drug cost, and nurse labor. Clinical investigation ovf those alternative dosage regimens would be required before implementation.
The in vivo mechanistic static model (IMSM) is an effective method to predict the magnitude of drug-drug interactions (DDIs) mediated by cytochromes.
The aim of this study was to extend the IMSM ...paradigm to DDIs mediated by organic anion transporting polypeptide (OATP) 1Bs, breast cancer resistance protein (BCRP) and cytochrome 2C8.
First, a generic model for this kind of interaction was established, and a literature search was then conducted to retrieve the area under the concentration-time curve (AUC) ratio of a large set of DDIs involving OATP1B1, OATP1B3, BCRP and cytochromes 2C8 or 3A4. The model was fitted to the data to estimate the characteristic parameters (contribution ratios CRs and inhibition or induction potencies IXs) by nonlinear regression, and the model was qualified by external validation on a different dataset. Lastly, the model was used to identify the risks of overexposure by DDIs of this type.
A total of 27 substrates, 26 inhibitors, 3 inducers and 3 genetic variants were considered in the regression analysis. The number of observations (AUC ratios, denoted as R
) was 101. Forty-six CRs and 47 IXs were estimated. The proportions of predictions within 0.67- to 1.5-fold and 0.5- to twofold R
were 90% and 99%, respectively, for the internal validation, and 78% and 96%, respectively, for the external validation. The median fold-error was 1.03 (the ideal value is 1). The interquartile range of fold-error was 0.31, and the relative standard error of parameter estimates was, at most, 17%.
The IMSM approach was successfully extended to DDIs mediated by OATP1Bs, BCRP and cytochromes 2C8 or 3A4. The method revealed good predictive performances by internal and external validation.
Population pharmacokinetic (PK) modeling is a widely used approach to analyze PK data obtained from groups of individuals, in both industry and academic research. The approach can also be used to ...analyze pharmacodynamic (PD) data and pooled PK/PD data. There are 2 main families of population PK methods: parametric and nonparametric. The objectives of this article are to present an overview of nonparametric methods used in population pharmacokinetic modeling and to explain their specific characteristics to inform scientists and clinicians about their potential value for data analysis, simulation, dosage design, and therapeutic drug monitoring (TDM). Nonparametric methods have several interesting characteristics for population PK analysis, including computation of exact likelihoods, the ability to accommodate parameter probability distributions of any shape (eg, non-Gaussian), and to detect subpopulations and outliers. Nonparametric population methods are also highly relevant for model-based TDM and design of individualized drug dosage regimens. Several algorithms have been developed to estimate model parameter values within an individual and compute that individual's dosage to achieve target drug exposure with maximum precision and accuracy. Nonparametric modeling methods for both population and individual PK analysis are available under user-friendly packages.
Rifamycins are widely used for treating mycobacterial and staphylococcal infections. Drug-drug interactions (DDI) caused by rifampicin (RIF) are a major issue. We used a model-based approach to ...predict the magnitude of DDI with RIF and rifabutin (RBT) for 217 cytochrome P450 (CYP) substrates. On average, DDI caused by low-dose RIF were twice as potent as those caused by RBT. Contrary to RIF, RBT appears unlikely to cause severe DDI, even with sensitive CYP substrates.
The magnitude of drug-drug interactions mediated by cytochrome P450 (CYP) may depend on the genotype of polymorphic cytochromes. The objective of this study was to identify drug-drug interactions ...with greater magnitude in CYP variant groups than in extensive metabolizers.
The in-vivo mechanistic static model was used to predict the area under the curve ratio of drug-drug interactions. Five cytochromes (CYP3A4/5, 2D6, 2C9, 2C19, 1A2) and five groups of genotypes for each polymorphic cytochrome (CYP2D6, 2C9, 2C19) were considered. The area under the curve ratios were calculated for all combinations and all genotypes for 196 substrates and 96 inhibitors. Among the strongest interactions (area under the curve ratio greater than 5), two levels of gene sensitivity of drug-drug interactions were defined: the intermediate sensitivity, with a three- to five-fold stronger interaction in genotype groups other than in extensive metabolizers, and the high sensitivity, with a more than five-fold stronger interaction than in genotype groups other than extensive metabolizers.
A red list of 104 interactions with a sensitivity greater than 3, involving 13 substrates and 24 interactors was obtained. There were 59 and 45 cases of high and intermediate sensitivity, respectively. The genotypes associated with a high sensitivity were CYP2D6 *3-8 *3-8 (sensitivity up to 24.3) and CYP2C19 *2-3*2-3 (sensitivity up to 37.8).
A cytochrome polymorphism may lead to major drug-drug interactions in poor metabolizers, while these interactions may not be significant in extensive metabolizers. Among the 104 cases studied, the interaction could be of ca. 30-fold larger magnitude in the worst case. Genotyping of the patient and/or therapeutic drug monitoring of the substrate should be carried out when an association mentioned in the red list is prescribed. The concept of gene sensitivity of drug-drug interactions appears promising for the development of precision medicine.
The indications of daptomycin have been extended to off-label indications including prosthesis-related infection, and bone and joint infection (BJI). However, efficacy and safety have not been ...thoroughly demonstrated compared with the standard of care. This systematic review and meta-analysis aimed to compare the treatment effect of daptomycin and glycopeptides for complicated infections.
MEDLINE, Embase and Web of Science were searched for randomized controlled trials (RCTs) comparing daptomycin and standard of care for Gram-positive infections, published until 30 June 2021. The primary outcome was defined as all-cause mortality. Secondary outcomes were clinical and microbiological success. The main safety outcome was any severe adverse event (SAE) (grade ≥3).
Overall, eight RCTs were included in the meta-analysis, totalling 1095 patients. Six (75%) were in complicated skin and soft-structure infections, one (12.5%) in bacteraemia and one (12.5%) in a BJI setting. Six RCTs used vancomycin as a comparator and two used either vancomycin or teicoplanin. All-cause mortality and clinical cure were not different between groups. The microbiological cure rate was superior in patients who received daptomycin risk ratio (RR) = 1.17 (95% CI: 1.01-1.35). The risk of SAEs RR = 0.57 (95% CI: 0.36-0.90) was lower in the daptomycin arm.
While daptomycin is associated with a significantly lower risk of SAEs and a better microbiological eradication, substantial uncertainty remains about the best treatment strategy in the absence of good-quality evidence, especially in bacteraemia and endocarditis where further RCTs should be conducted.
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