Dataset Information

Treatment by Posaconazole Tablets, Compared to Posaconazole Suspension, Does Not Reduce Variability of Posaconazole Trough Concentrations.

ABSTRACT: The delayed-release tablet formulation of posaconazole (POS-tab) results in higher plasma POS trough concentrations (C_min) than the oral suspension (POS-susp), which raises the question of the utility of therapeutic drug monitoring (TDM). We aimed to compare the variability of the POS C_min for the two formulations and identify determinants of the POS-tab C_min and its variability. Demographic, biological, and clinical data from 77 allogeneic hematopoietic stem cell transplant patients (874 C_min) treated with POS-tab (n?=?41), POS-susp (n?=?29), or both (n?=?7) from January 2015 to December 2016 were collected retrospectively. Interpatient and within-subject coefficients of variation (CVs) of the C_min adjusted to dose (D) were calculated for each formulation. Between-group comparisons were performed using a linear mixed effects model. The POS C_min was higher for the tablet than for the suspension (median [25th-75th percentile]: 1.8 [1.2-2.4] mg/liter versus 1.2 [0.7-1.6] mg/liter, P?P?=?0.7), whereas within-subject CVs were 39.7 and 44.9%, respectively (P?=?0.3). Univariate analysis showed that age and treatment by POS-tab were significantly and positively associated with the POS C_min, whereas diarrhea was associated with a diminished POS C_min Multivariate analysis identified treatment with POS-tab and diarrhea as independent factors of the POS C_min, with a trend toward a lower impact of diarrhea during treatment with POS-tab (P?=?0.07). Despite increased POS exposure with the tablet formulation, the variability of the POS C_min was not significantly lower than that of the suspension. This suggests that TDM may still be useful to optimize tablet POS therapy.

SUBMITTER: Gautier-Veyret E

PROVIDER: S-EPMC6761514 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Treatment by Posaconazole Tablets, Compared to Posaconazole Suspension, Does Not Reduce Variability of Posaconazole Trough Concentrations.

Gautier-Veyret Elodie E Bolcato Léa L Roustit Matthieu M Weiss Stéphanie S Tonini Julia J Brenier-Pinchart Marie-Pierre MP Cornet Muriel M Thiebaut-Bertrand Anne A Stanke-Labesque Françoise F

Antimicrobial agents and chemotherapy 20190923 10

The delayed-release tablet formulation of posaconazole (POS-tab) results in higher plasma POS trough concentrations (Cmin) than the oral suspension (POS-susp), which raises the question of the utility of therapeutic drug monitoring (TDM). We aimed to compare the variability of the POS Cmin for the two formulations and identify determinants of the POS-tab Cmin and its variability. Demographic, biological, and clinical data from 77 allogeneic hematopoietic stem cel ...[more]

PMID: 31358587

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Project description:Biochemical drug screening by liquid chromatography-tandem mass spectrometry in plasma is an accurate method for the quantification of plasma concentrations of antihypertensive medications in patients with hypertension. Trough concentrations could possibly be used as drug-specific cutoff values in the biochemical assessment of (non-)adherence. We performed a literature review and meta-analysis of pharmacokinetic studies to determine plasma trough concentrations of amlodipine, hydrochlorothiazide, and valsartan. PubMed was searched for pharmacokinetic studies up to September 2020. Eligible studies reported steady-state mean trough concentration and their variance. Pooled trough concentrations were estimated using a three-level random effects meta-analytic model. Moderator analyses were performed to explore sources of heterogeneity. One thousand three hundred eighteen potentially relevant articles were identified of which 45 were eligible for inclusion. The pooled mean trough concentration was 9.2 ng/mL (95% CI, 7.5-10.8) for amlodipine, 41.0 ng/mL (95% CI, 17.4-64.7) for hydrochlorothiazide, and 352.9 ng/mL (95% CI, 243.5-462.3) for valsartan. Substantial heterogeneity was present for all 3 pooled estimates. Moderator analyses identified dosage as a significant moderator for the pooled trough concentration of amlodipine (β1=0.9; P<0.05), mean age, and mean body weight for the mean trough concentration of hydrochlorothiazide (β1=2.2, P<0.05, respectively, β1=-4.0, P<0.05) and no significant moderators for valsartan. Plasma trough concentrations of amlodipine, hydrochlorothiazide, and valsartan, measured with liquid chromatography-tandem mass spectrometry, are highly heterogeneous over the different studies. Use of the pooled trough concentration as a cutoff in the biochemical assessment of adherence can result in inaccurate diagnosis of (non-)adherence, which may seriously harm the patient-physician relationship, and is therefore not recommended.

Project description:The objective of this study was to explore the following aspects of teicoplanin use in patients with hematological malignancy: early attainment of target trough concentrations with current high-dose teicoplanin regimens, variability in unbound teicoplanin fractions, factors associated with observed total and unbound trough concentrations, efficacy and toxicity, and renal function estimation. This was a single-center, prospective study. Samples for determination of trough concentrations were taken on days 3, 4, 7, and 10. Total and unbound teicoplanin concentrations were determined using validated high-performance liquid chromatography methods. Regression analyses were used to identify the factors associated with the trough concentration. Thirty teicoplanin-treated adults with hematological malignancy were recruited. Despite the use of dosages higher than the conventional dosages, the proportions of patients with a trough concentration of ?20 mg/liter at 48 h and at 72 h were 16.7% and 37.9%, respectively. Renal function was significantly negatively associated with total trough concentrations at 48 h and 72 h (P < 0.05). For an average hematological malignancy patient (creatinine clearance = 70 ml/min), sequential loading doses of at least 12 mg/kg of body weight may be needed to achieve early adequate exposure. In the absence of measured creatinine clearance, estimates obtained using the Cockcroft-Gault (total body weight) equation could prove to be an acceptable surrogate. The unbound fractions of teicoplanin were highly variable (3.4 to 18.8%). Higher unbound fractions were observed in patients with low serum albumin concentrations. Teicoplanin was well tolerated. Teicoplanin loading doses higher than those in current use appear to be necessary. Increased dosing is needed in patients with increased renal function. The high variability in protein binding supports the contention for therapeutic drug monitoring of unbound teicoplanin concentrations. (This study has been registered with EudraCT under registration no. 2013-004535-72.).

Dataset Information

Treatment by Posaconazole Tablets, Compared to Posaconazole Suspension, Does Not Reduce Variability of Posaconazole Trough Concentrations.

Publications

Treatment by Posaconazole Tablets, Compared to Posaconazole Suspension, Does Not Reduce Variability of Posaconazole Trough Concentrations.

Similar Datasets

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