Phenylacetate pharmacokinetics based on iterative two-stage population analysis.
OBJECTIVE
To determine the population pharmacokinetics of phenylacetate using iterative two-stage analysis implemented with ADAPT 11 software.


METHODS
United States government research hospital.


METHODS
Retrospective pharmacokinetic analysis.


METHODS
Sixty-seven patients with refractory solid tumors.


METHODS
Subjects received from 1-10 courses/individual (total 141 courses) of therapy with either twice-daily administration or continuous infusions of phenylacetate.


RESULTS
Extensive plasma concentration measurements were performed after the initial dose or start of infusion, with sparse sampling during subsequent courses of therapy. Phenylacetate plasma concentration-time profiles were described by a one-compartment, capacity-limited clearance model with incorporation of parameters to describe extent of induction of clearance and the rate of induction. Median estimates for volume of distribution, maximum rate of drug elimination, Michaelis-Menten constant, and induction factor, and rate of onset of induction of drug clearance were 0.33 (0.26, 0.48) L/kg, 21.8 (16.3, 28.0) mg/kg/hour, 94.6 (48.8, 153.0) mg/L, 1.28 (1.06, 1.66), and 0.0038 (0.0019, 0.0058) hour(-1), respectively.


CONCLUSIONS
The results of this study are similar to previous pharmacokinetic evaluations using the Abbottbase PKS system but suggest that earlier analyses were suboptimal.
Clinical Center Pharmacy Department, National Institutes of Health, Bethesda, Maryland, USA.
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Burstein
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Reed
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Tompkins
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Venzon
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Figg
D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D010648:Phenylacetates / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D011153:Population; D012189:Retrospective Studies; D012494:Sampling Studies; D013056:Spectrophotometry, Ultraviolet
D000964:Antimetabolites, Antineoplastic; D010648:Phenylacetates; C025136:phenylacetic acid