Prediction of Unbound Serum Valproic Acid Concentration by Using In Vivo Binding Parameters

Kodama, Yasuo; Kuranari, Masae; Tsutsumi, Kimiko; Kimoto, Hiroo; Fujii, Isao; Takeyama, Masaharu

doi:10.1097/00007691-199210000-00001

Cited by 13 publications

(12 citation statements)

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“…The median (range) simulated free fraction in our patients was 11 (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) % and 14 (9-41) %, for doses of 1 and 2 g, respectively. The simulated trough concentration and time > MIC following a single dose of ceftriaxone at 1 or 2 g in patients with different degrees of renal function are presented in Table 4.…”

Section: Dosing Simulationsmentioning

confidence: 72%

“…The free concentrations ( C free ) were estimated from total concentrations ( C tot ) using in vivo binding parameters of ceftriaxone [13] and the following equation, as described by Kodama et al . [14]: …”

Section: Methodsmentioning

confidence: 99%

“…Aa antibacterial activity is rather dependent on free concentrations, we computed them from observed concentrations. The free concentrations (Cfree) were estimated from total concentrations (Ctot) using in vivo binding parameters of ceftriaxone [13] and the following equation, as described by Kodama et al [14]:…”

Section: Dosing Simulationsmentioning

confidence: 99%

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Population pharmacokinetics of ceftriaxone in critically ill septic patients: a reappraisal

Garot

Respaud

Lanotte

et al. 2011

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Intensive care unit patients exhibit altered pharmacokinetics for many drugs and suboptimal exposure may be detrimental. • Despite frequent use of ceftriaxone in critically ill patients, its pharmacokinetics have not been studied in large cohorts of critically ill patients. • Population pharmacokinetic analysis provides pharmacokinetic parameter estimates, estimates of inter-individual and intra-individual variability in these parameters and allows patient characteristics explaining inter-individual variability to be quantified. • Coupled with pharmacodynamic analysis, this approach can help in simulating an optimal dosing regimen based on individual characteristics. WHAT THIS STUDY ADDS • Our population model characterized the pharmacokinetic profile of ceftriaxone in patients with highly variable characteristics • Creatinine clearance was identified as the main covariate influencing ceftriaxone pharmacokinetics, particularly for high values. Haemofiltration had no effect. • Model-based simulations showed that the risk of being under threshold concentrations is low for infections due to common pathogens, but exists in patients with high glomerular filtration rates. AIMS To investigate the population pharmacokinetics of ceftriaxone in critically ill patients suffering from sepsis, severe sepsis or septic shock. METHODS Blood samples were collected at preselected times in 54 adult patients suffering from sepsis, severe sepsis or septic shock in order to determine ceftriaxone concentrations using high-performance liquid chromatography-ultraviolet detection. The pharmacokinetics of ceftriaxone were assessed on two separate occasions for each patient: on the second day of ceftriaxone therapy and 48 h after catecholamine withdrawal in patients with septic shock, or on the fifth day in patients with sepsis. The population pharmacokinetics of ceftriaxone were studied using nonlinear mixed effects modelling. RESULTS The population estimates (interindividual variability; coefficient of variation) for ceftriaxone pharmacokinetics were: a clearance of 0.88 l h-1 (49%), a mean half-life of 9.6 h (range 0.83-28.6 h) and a total volume of distribution of 19.5 l (range 6.48-35.2 l). The total volume of distribution was higher than that generally found in healthy individuals and increased with the severity of sepsis. However, the only covariate influencing the ceftriaxone pharmacokinetics was creatinine clearance. Dosage simulations showed that the risk of ceftriaxone concentrations dropping below the minimum inhibitory concentration threshold was low. CONCLUSIONS Despite the wide interpatient variability of ceftriaxone pharmacokinetic parameters, our results revealed that increasing the ceftriaxone dosage when treating critically ill patients is unnecessary. The risk of ceftriaxone concentrations dropping below the minimum inhibitory concentration threshold is limited to patients with high glomerular filtration rates or infections with high minimum inhibitory concentration pathogens (...

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Section: Dosing Simulationsmentioning

confidence: 72%

Section: Methodsmentioning

confidence: 99%

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Population pharmacokinetics of ceftriaxone in critically ill septic patients: a reappraisal

Garot

Respaud

Lanotte

et al. 2011

Brit J Clinical Pharma

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“…Valproate (VPA) is a first-line broad-spectrum antiepileptic drug (AED), which is a branched-chain fatty acid, highly bound to plasma albumin. The binding is both saturable (8) and influenced by a range of physiologic factors (9,10), as well as by other drugs (11,12). Although there are previous studies of the distribution of VPA to CSF (13)(14)(15) and brain (16)(17)(18) in humans, the time-course of distribution to the central nervous system (CNS) has not been investigated.…”

Section: Discussionmentioning

confidence: 99%

Distribution of Valproate to Subdural Cerebrospinal Fluid, Subcutaneous Extracellular Fluid, and Plasma in Humans: A Microdialysis Study

et al. 2001

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Summary We sought to study the time course of the distribution of valproate (VPA) to subdural cerebrospinal fluid (CSF) in relation to subcutaneous extracellular fluid (ECF) and plasma after a single oral dose and to study the distribution to these three compartments under steady‐state conditions. Microdialysis was used to estimate unbound VPA concentrations in subdural CSF and subcutaneous ECF, and blood samples were drawn for estimation of total and unbound VPA plasma concentrations in four patients with drug‐resistant partial epilepsy undergoing presurgical evaluation with subdural EEG monitoring. Three patients were given a single oral dose of VPA, and one patient was receiving regular VPA treatment. VPA was analyzed by gas chromatography with flame ionization detection. The distribution of VPA to subdural CSF was rapid (Tmax, 3.5 h in two patients and 5.5 h in one patient) and subject to a minor delay in all three patients compared with that in the subcutaneous tissue ECF (Tmax, 2.5 h in all three patients), which in turn exhibited no evidence of a distribution delay compared with plasma. Subdural CSF levels of VPA were slightly lower than subcutaneous ECF levels (mean ratio, 0.78) and unbound plasma levels (mean ratio, 0.91). VPA rapidly enters the subdural CSF in unbound concentrations marginally lower than those obtained in subcutaneous ECF and plasma. These findings provide a pharmacokinetic rationale for acute administration of VPA. The good correlation between VPA concentrations in subcutaneous ECF and subdural CSF indicates that estimation of unbound VPA concentrations in subcutaneous tissue using microdialysis sampling has the potential to be useful for monitoring purposes.

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“…The free concentrations (C free ) were estimated from the total concentrations ( C tot ) using in vivo binding parameters of CTX and the following equation described by Kodama et al [19]:The following binding of CTX was used: the total concentration of protein binding sites (nP) 517 μmol l −1 and the binding affinity constant (K aff ) 0.0367 l μmol −1. …”

Section: Methodsmentioning

confidence: 99%

Changes in ceftriaxone pharmacokinetics/pharmacodynamics during the early phase of sepsis: a prospective, experimental study in the rat

Selmi¹,

Loriga²,

Vitali³

et al. 2016

J Transl Med

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BackgroundSepsis is characterized by the loss of the perm-selectivity properties of the glomerular filtration barrier (GFB) with consequent albuminuria. We examined whether the pharmacokinetics–pharmacodynamics (PK/PD) of ceftriaxone (CTX), an extensively protein-bound 3rd generation cephalosporin, is altered during early sepsis and whether an increase in urinary loss of bound-CTX, due to GFB alteration, can occur in this condition.MethodsA prospective, experimental, randomized study was carried out in adult male Sprague–Dawley rats. Sepsis was induced by cecal ligation and puncture (CLP). Rats were divided into two groups: Sham-operated and CLP. CTX (100 mg i.p., equivalent to 1 g dose in humans) was administered in order to measure plasma and lung CTX concentrations at several time-points: baseline and 1, 2, 4 and 6 h after administration. CTX was measured by High Performance Liquid Chromatography (HPLC). The morphological status of the sialic components of the GFB barrier was assessed by lectin histo-chemistry. Monte Carlo simulation was performed to calculate the probability of target attainment (PTA >90%) for 80 and 100% of Tfree > minimum inhibitory concentration (MIC) for 80 and 100% of dosing interval.Measurements and main resultsAfter CLP, sepsis developed in rats as documented by the growth of polymicrobial flora in the peritoneal fluid (≤1 × 101 CFU in sham rats vs 5 × 104–1 × 105 CFU in CLP rats). CTX plasma concentrations were higher in CLP than in sham rats at 2 and 4 h after administration (difference at 2 h was 47.3, p = 0.012; difference at 4 h was 24.94, p = 0.004), while lung penetration tended to be lower. An increased urinary elimination of protein-bound CTX occurred (553 ± 689 vs 149 ± 128 mg/L, p < 0.05; % of bound/total CTX 22 ± 6 in septic rats vs 11 ± 4 in sham rats, p < 0.01) and it was associated with loss of the GFB sialic components. According to Monte Carlo simulation a PTA > 90% for 100% of the dosing interval was reached neither for sham nor CLP rats using MIC = 1 mg/L, the clinical breakpoint for Enterobacteriacee.ConclusionsSepsis causes changes in the PK of CTX and an alteration in the sialic components of the GFB, with consequent loss of protein-bound CTX. Among factors that can affect drug pharmacokinetics during the early phases of sepsis, urinary loss of both free and albumin–bound antimicrobials should be considered.

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Prediction of Unbound Serum Valproic Acid Concentration by Using In Vivo Binding Parameters

Cited by 13 publications

References 0 publications

Population pharmacokinetics of ceftriaxone in critically ill septic patients: a reappraisal

Population pharmacokinetics of ceftriaxone in critically ill septic patients: a reappraisal

Distribution of Valproate to Subdural Cerebrospinal Fluid, Subcutaneous Extracellular Fluid, and Plasma in Humans: A Microdialysis Study

Changes in ceftriaxone pharmacokinetics/pharmacodynamics during the early phase of sepsis: a prospective, experimental study in the rat

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