Monitoring for valproate and phenytoin toxicity in hypoalbuminaemia: A retrospective cohort study

Arushi Madan; Peter J Donovan; Tracy Risetto; Helen Trenerry; Cecilie M Lander

doi:10.1111/bcp.14853

Monitoring for valproate and phenytoin toxicity in hypoalbuminaemia: A retrospective cohort study

Br J Clin Pharmacol. 2021 Nov;87(11):4341-4353. doi: 10.1111/bcp.14853. Epub 2021 May 4.

Authors

Arushi Madan^{1

2}, Peter J Donovan^{1

2}, Tracy Risetto³, Helen Trenerry³, Cecilie M Lander^{2

4}

Affiliations

¹ Clinical Pharmacology, Royal Brisbane & Women's Hospital, Brisbane, Australia.
² Faculty of Medicine, University of Queensland, Brisbane, Australia.
³ Queensland Medicines Advice and Information Service, Royal Brisbane & Women's Hospital, Brisbane, Australia.
⁴ Neurology, Royal Brisbane & Women's Hospital, Brisbane, Australia.

PMID: 33835518
DOI: 10.1111/bcp.14853

Abstract

Aims: Equations to calculate albumin-adjusted total concentrations have been validated to correlate with measured free concentrations for both phenytoin and valproate, but there is a lack of data to assess correlation with clinical outcomes. We aimed to assess the association of hypoalbuminaemia and albumin-adjusted total concentrations with concentration-dependent toxicity for phenytoin and valproate and review the impact on management decisions following concentration monitoring in hypoalbuminaemia.

Methods: Patients undergoing concentration monitoring for phenytoin or valproate between January and December 2018 were included. Patients were identified using a centralised laboratory database with data extracted from medical records.

Results: Total phenytoin concentrations were measured for 144 patients, with hypoalbuminaemia (≤30 g L^-1 ) recorded in 59 (41%) patients. Albumin-adjusted phenytoin concentration >20 mg L^-1 was associated with increased neurological adverse effects (77% vs. 43%, P < .001). On logistic regression, higher albumin-adjusted phenytoin concentration was an independent risk factor for neurotoxicity (OR 1.06, 95% CI 1.01-1.12, P = .011). Total valproate concentrations were measured for 383 patients, with hypoalbuminaemia (≤30 g L^-1 ) noted in 53 (14%) patients. For the valproate cohort, hypoalbuminaemia (42% vs. 28%, P = .039) and albumin-adjusted valproate concentration >100 mg L^-1 (49% vs. 23%, P < .001) were both associated with increased neurotoxicity. On multiple logistic-regression, valproate daily dose (aOR = 1.01, 95% CI 1.00-1.02, P = .006) and albumin-adjusted valproate concentration (aOR 1.01, 95% CI 1.00-1.02, P = .033) were independent risk factors for neurotoxicity after accounting for confounders.

Conclusion: While measuring free drug concentrations in hypoalbuminaemia would be ideal, the adjustment equations can help identify vulnerable patients needing further assessment of potential concentration-dependent toxicity.

Keywords: hypoalbuminaemia; phenytoin; therapeutic drug monitoring; toxicity; valproate.

MeSH terms

Cohort Studies
Humans
Hypoalbuminemia*
Phenytoin / adverse effects
Retrospective Studies
Valproic Acid* / adverse effects

Substances

Valproic Acid
Phenytoin