Elevated Free Fractions of Valproic Acid in a Heart Transplant Patient with Hypoalbuminemia

Haroldson, Jeffrey A; Kramer, Linda E; Wolff, Denise L; Lake, Kathleen D.

doi:10.1345/aph.19147

Cited by 37 publications

(28 citation statements)

References 20 publications

(2 reference statements)

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“…Saturation of drug binding to plasma constituents, blood cells, and extravascular tissue leading to nonlinear pharmacokinetics is relatively common and has been well described for several drugs, including valproic acid (19). However, the phenomenon of a dosedependent decrease in systemic exposure as seen here with i.v.-administered UCN-01 is highly unusual.…”

Section: Discussionmentioning

confidence: 76%

Effects of α1-Acid Glycoprotein on the Clinical Pharmacokinetics of 7-Hydroxystaurosporine

Sparreboom¹,

Chen²,

Acharya³

et al. 2004

Clinical Cancer Research

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Objective: UCN-01 (7-hydroxystaurosporine) is a small molecule cyclin-dependent kinase modulator currently under clinical development as an anticancer agent. In vitro studies have demonstrated that UCN-01 is strongly bound to the acute-phase reactant ␣ 1 -acid glycoprotein (AAG). Here, we examined the role of protein binding as a determinant of the pharmacokinetic behavior of UCN-01 in patients.Experimental Design: Pharmacokinetic data were obtained from a group of 41 patients with cancer receiving UCN-01 as a 72-hour i.v. infusion (dose, 3.6 to 53 mg/m 2 /day). Results: Over the tested dose range, total drug clearance was distinctly nonlinear (P ‫؍‬ 0.0076) and increased exponentially from 4.33 mL/hour (at 3.6 mg/m 2 /day) to 24.1 mL/hour (at 54 mg/m 2 /day). As individual values for AAG increased, values for clearance decreased in a linear fashion (R 2 ‫؍‬ 0.264; P ‫؍‬ 0.0008), although the relationship was shallow, and the data showed considerable scatter. Interestingly, no nonlinearity in the unbound concentration (P ‫؍‬ 0.083) or fraction at the peak plasma concentration of UCN-01 was apparent (P ‫؍‬ 0.744). Conclusion:The results suggest the following: (1) that extensive binding to AAG may explain, in part, the unique pharmacokinetic profile of UCN-01 described previously with a small volume of distribution and slow systemic clearance, and (2) that measurement of total UCN-01 concentrations in plasma is a poor surrogate for that of the pharmacologically active fraction unbound drug.

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Section: Discussionmentioning

confidence: 76%

Effects of α1-Acid Glycoprotein on the Clinical Pharmacokinetics of 7-Hydroxystaurosporine

Sparreboom¹,

Chen²,

Acharya³

et al. 2004

Clinical Cancer Research

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“…In cases of neurotoxicity previously described in hypoalbuminemic patients, with high free concentrations of valproic acid (8,9), normalization of the total concentration of the drug would have offered clinically useful information (C N >100 mg / L), suggesting a decrease of the doses.…”

Section: Discussionmentioning

confidence: 99%

A Theoretical Method for Normalizing Total Serum Valproic Acid Concentration in Hypoalbuminemic Patients

Hermida

Tutor

2005

J Pharmacol Sci

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Abstract. In patients with hypoalbuminemia, the total serum concentration of valproic acid may offer poor clinical information; however, very few clinical laboratories routinely analyze the free concentration of the drug. The aim of this study was to design a procedure to normalize the total concentration of valproic acid according to the level of serum albumin and using previously published free fraction values. In 121 adult patients, with albumin levels of 18 -41 g / L, the total concentration of valproic acid was normalized using the derived equation: C N = a H C H / 6.5, where a H is the free fraction of the drug corresponding to the patient's particular albuminemia and C H is the total concentration of valproic acid. The value of 6.5 corresponds to the free fraction of the drug for a serum albumin of 42 g / L (percentile 50 of the reference range). For total concentrations lower than 75 mg / L, the predicted normalized valproic acid concentrations were reasonably concordant with the observed normalized concentrations calculated using the data from a protein-binding study. In a significant number of cases, subtherapeutic concentrations of the drug became therapeutic and even supratherapeutic when corrected according to the albumin levels. Furthermore, cases with therapeutic drug concentrations frequently became supratherapeutic when normalized. The limitations and clinical aplications of the proposed formula for normalizing the total concentration of valproic acid are presented. It is concluded that it may be useful for the posological management of hypoalbuminemic patients when the free concentration of the drug is not available, and decisions have to be made based on the total serum concentration.

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“…However, mixed success stories of clear correlation between free concentration of VPA with its pharmacological response (also complicated by formation of active metabolites) and clinical significance have been reported 71,73. Free VPA concentration has been reported to correlate well with its toxicity, especially in the case of hypoalbuminemic patients,74,75 and due to its NTI and nonlinear PPB, free VPA concentration is recommended to be monitored in patients.…”

Section: Relevance Of Ppb In Clinical Settingmentioning

confidence: 99%

Plasma protein binding: From discovery to development

Bohnert

Gan

2013

Journal of Pharmaceutical Sciences

306

257

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Elevated Free Fractions of Valproic Acid in a Heart Transplant Patient with Hypoalbuminemia

Abstract: This case report suggests that appropriate monitoring of unbound drug concentrations of VPA may prevent unrecognized concentration-related adverse effects. Awareness of the pharmacokinetic relationship and adverse effects of VPA will aid clinicians in identifying the etiology of symptoms.

Cited by 37 publications

References 20 publications

Effects of α1-Acid Glycoprotein on the Clinical Pharmacokinetics of 7-Hydroxystaurosporine

Effects of α1-Acid Glycoprotein on the Clinical Pharmacokinetics of 7-Hydroxystaurosporine

A Theoretical Method for Normalizing Total Serum Valproic Acid Concentration in Hypoalbuminemic Patients

Plasma protein binding: From discovery to development

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