Pharmacokinetic characterization of baclofen in patients with chronic kidney disease: dose adjustment recommendations

Vlavonou, Raphaël; Perreault, Marc M.; Barrière, Olivier; Shink, Éric; Tremblay, Pierre-Olivier; Larouche, Richard; Pichette, Vincent; Tanguay, Mario

doi:10.1002/jcph.247

Cited by 44 publications

(25 citation statements)

References 18 publications

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“…Similarly, to the study of Marsot et al , an influence of CLCr was observed on baclofen CL/F but without significantly improving the fit. The impact of renal failure has been clearly described by Vlavonou et al showing that the systemic clearance of baclofen was reduced by 34, 49 and 63% in mild, moderate and severe renal failure, respectively. A reduction of 1/3, 1/2 and 2/3 of the baclofen daily dose in patients with mild, moderate and severe renal failure was advised to achieve baclofen exposure comparable to that observed in healthy subjects with normal renal function.…”

Section: Discussionmentioning

confidence: 90%

Population pharmacokinetics of oral baclofen at steady‐state in alcoholic‐dependent adult patients

Chevillard

Sabo

Tod

et al. 2017

Fundamemntal Clinical Pharma

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Baclofen has been proposed for few years to help treating alcohol dependence at higher doses than those used in neurology. Baclofen pharmacokinetics has been previously well described at low oral or intravenous doses but remains poorly investigated with such high oral doses. We here describe dose regimens of baclofen in 143 alcohol-dependent patients treated with steady-state oral doses of baclofen. Plasma baclofen levels were measured in blood samples using liquid chromatography coupled with tandem mass spectrometry. One hundred and forty-nine baclofen concentrations were sampled 30 min to 15 h after the last dose, and baclofen pharmacokinetics was determined using population pharmacokinetics approach. Our population, whose average age and BMI were 51.5 years and 25.5 kg/m , respectively, was composed of two-thirds of men. Daily baclofen doses ranged from 15 to 250 mg and 26% were higher than 120 mg. A one-compartment model with first-order absorption and elimination allowed to determine mean values for clearance (CL/F), volume of distribution (V/F) and absorption rate constant at 8.0 L/h, 44.5 L and 2.23 h , respectively. Inter-individual variability on CL/F and V/F was 27.4 and 86% for the parameters. None of the demographic and biological covariates significantly decreased inter-individual variability. A proportional relationship between oral dose and plasma baclofen exposure indicated a linear pharmacokinetics of baclofen even at doses over 120 mg/day. Our large population study evidenced a linear pharmacokinetics of oral baclofen even at high daily doses with an inter-individual variability of baclofen exposure that could not be explained by demographic and biological data.

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Section: Discussionmentioning

confidence: 90%

Population pharmacokinetics of oral baclofen at steady‐state in alcoholic‐dependent adult patients

Chevillard

Sabo

Tod

et al. 2017

Fundamemntal Clinical Pharma

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“…In healthy volunteers a high correlation between the apparent renal clearance of baclofen and the creatinine clearance was described ( 12 ). This has been confirmed by a study including four groups of patients with different kidney disease stages ( 30 ). The authors found the following significant linear relationship ( R 2 = 0.67, p < 0.0001) between baclofen clearance (CL/F) and creatinine clearance (CrCL):…”

Section: Metabolism and Eliminationmentioning

confidence: 56%

Pharmacokinetic Studies of Baclofen Are Not Sufficient to Establish an Optimized Dosage for Management of Alcohol Disorder

2018

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Several clinical randomized trials have evaluated the interest of baclofen in patients with alcohol use disorder. Depending on the study design and the inclusion criteria, the results vary from enthusiastic to pessimistic. However, all researchers and practitioners agree that they observe a wide variability in the therapeutic responses. If some patients exhibit a clinical response at low doses, ~40 mg daily, others require doses higher than 300 mg. Before multiplying new other clinical trials, it is required to better understand the reason of this variability. Several mechanisms may be responsible for providing different effects with an identical daily dose. Especially, each pharmacokinetic step, absorption, distribution, metabolism, and elimination may lead to a different exposure after an identical dose. Absorption may imply a saturation process limiting the bioavailability (F) of baclofen in some patients. In such a situation, food, or drug-drug interaction can change the absorption rate of the drug modifying the maximum concentration (Cmax) and area under the curve (AUC). Distribution and brain penetration across the blood-brain barrier may depend of a specific transporter. These transporters are subject to genetic polymorphism and drug-drug interaction. Finally, elimination may be increased by a specific secretion pathway. This review describes all available pharmacokinetic data on these different pharmacokinetics steps aiming to identify the source of variability of baclofen in patients with alcohol use disorder.

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“…9 However, this report does not consider the potential difference in pharmacokinetics for a patient who is on chronic baclofen therapy. [2][3][4][5][6]10 It is unclear if depot lipophilic stores of drug or the chronic saturation of plasma protein and tissuebinding sites is the mechanism responsible for the reported toxicities in this patient population. Moreover, patients with severe chronic renal disease have been reported to have increased susceptibility to baclofen toxicity, despite levels that are within defined "range."…”

Section: Discussionmentioning

confidence: 99%

Baclofen Toxicity Responsive to Hemodialysis in a Pediatric Patient with Acute Kidney Injury

Gee

Outsen

Becknell

et al. 2015

J Pediatr Intensive Care

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Background?Baclofen (para-chlorophenyl-gamma-aminobutyric acid) is widely used for its therapeutic effect of providing muscle relaxation from the persistent muscle spasms and posturing often related to spinal and central nervous system injuries. However, baclofen is also a potent neuronal depressant which is most evident in cases of toxicity. In severe toxicity, respiratory failure and obtundation may occur. Case-diagnosis/treatment?We present the case of a neurologically devastated 16-year-old on chronic baclofen therapy for bilateral spastic cerebral palsy (Gross Motor Function Classification System level V) who presented with fever, leukocytosis, and hypotension. Initial management with fluid resuscitation and antimicrobials for presumed infection did initially improve the patient's mental status; however, he subsequently became comatose later during the same hospitalization. Comprehensive diagnostic studies and infectious work-up did not reveal an etiology. Upon further examination of history, acute kidney injury from chronic nonsteroidal use and complicated by vancomycin toxicity was suspected to cause acute baclofen toxicity. The patient underwent a single run of hemodialysis with resultant neurologic improvement and later laboratory-confirmed toxic baclofen levels. Conclusion?Clinicians should consider possible acute baclofen toxicity in patients with impaired renal function who present with neurologic depression. Respiratory failure and mechanical ventilation, with its associated intensive care costs and complications, may be avoided with prompt treatment using hemodialysis.

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Pharmacokinetic characterization of baclofen in patients with chronic kidney disease: dose adjustment recommendations

Cited by 44 publications

References 18 publications

Population pharmacokinetics of oral baclofen at steady‐state in alcoholic‐dependent adult patients

Population pharmacokinetics of oral baclofen at steady‐state in alcoholic‐dependent adult patients

Pharmacokinetic Studies of Baclofen Are Not Sufficient to Establish an Optimized Dosage for Management of Alcohol Disorder

Baclofen Toxicity Responsive to Hemodialysis in a Pediatric Patient with Acute Kidney Injury

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