A Prospective Population Pharmacokinetic Study on Morphine Metabolism in Cancer Patients

Abstract

BackgroundOral and subcutaneous morphine is widely used for the treatment of cancer-related pain; however, solid pharmacokinetic data on this practice are lacking. Furthermore, it is largely unknown which factors contribute to the variability in clearances of morphine and its metabolites and whether morphine clearance is related to treatment outcome.MethodsBlood samples from 49 cancer patients treated with oral and/or subcutaneous morphine were prospectively collected and were used to develop a population pharmacokinetic model for morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). The influence of age, gender, renal function and several polymorphisms possibly related to the pharmacokinetics of the three compounds was investigated. In addition, the relation between treatment failure and morphine and metabolite clearances was explored.ResultsA one-compartment model including an extensive first-pass effect adequately described the data of morphine and its metabolites. Estimated mean area under the plasma concentration–time curve (AUC) ratios following oral versus subcutaneous administration were: M3G/morphine 29.7:1 vs. 11.1:1; M6G/morphine 5.26:1 vs. 1.95:1; and M3G/M6G 5.65:1 vs. 5.70:1. Renal function was significantly correlated with clearance of the metabolites, which increased 0.602 L/h per every 10 mL/min/1.73 m2 increase of estimated glomerular filtration rate (eGFR), reaching a plateau for eGFR >90 mL/min/1.73 m2. The clearance of morphine or its metabolites was not found to be correlated with treatment failure.ConclusionThe influence of age-, gender- and pharmacokinetic-related polymorphisms was not identified on the pharmacokinetics of morphine. Clearance of morphine or its metabolites was not found to explain treatment outcome; however, large variations in plasma concentrations of morphine, M3G and M6G support further studies on the relation between plasma concentrations and treatment outcome.Dutch Trial Register ID: NTR4369.Electronic supplementary materialThe online version of this article (doi:10.1007/s40262-016-0471-7) contains supplementary material, which is available to authorized users.

Opioids as Substrates and Inhibitors of the Genetically Highly Variable Organic Cation Transporter OCT1

“…These findings were confirmed and extended by a study of Fukuda et al, where pediatric patients with poor OCT1 transporter genotype showed significantly lower morphine plasma clearance (by 20%) than extensive OCT1 transporters. , Recently, an association between OCT1 genetic variants and morphine-related adverse effects in children has been reported by Balyan et al However, the data on morphine is not unequivocal. Two recent studies by Oosten et al and Nielsen et al did not show an association of OCT1 genotype and morphine pharmacokinetics.…”

“…22,23 Recently, an association between OCT1 genetic variants and morphinerelated adverse effects in children has been reported by Balyan et al 24 However, the data on morphine is not unequivocal. Two recent studies by Oosten et al 25 and Nielsen et al 26 did not show an association of OCT1 genotype and morphine pharmacokinetics.…”

Pharmacokinetic modeling of morphine and its glucuronides: Comparison of nebulization versus intravenous route in healthy volunteers

“…Indeed, most of the F I G U R E 2 Individual predictions of morphine (upper panels, a, b), morphine-3-glucuronide (M3G; middle panels, c, d) and morphine-6-glucuronide (M6G; lower panels, e, f) following intravenous (left panels, a, c, e) and nebulized (right panels, b, d, f) administration. IV, intravenous; NEB, nebulized published morphine parent-metabolite models used a specific volume of distribution for metabolites, 34 do not use transit compartments for metabolite production, 40,41 or were built for specific populations, such as morbid obesity in adults, 34 patients with cancer, 41 or neonates. 40 Although analgesically inactive, M3G has been reported to antagonize morphine and to produce stimulatory effects responsible for side effects, such as myoclonus, seizure, and allodynia.…”

“…In this study, the choice has been made to fix values that come from monolix estimation rather than following the literature. Indeed, most of the published morphine parent‐metabolite models used a specific volume of distribution for metabolites, 34 do not use transit compartments for metabolite production, 40,41 or were built for specific populations, such as morbid obesity in adults, 34 patients with cancer, 41 or neonates 40…”

No significant influence of OCT1 genotypes on the pharmacokinetics of morphine in adult surgical patients

“…Both in vitro and clinical studies have reported an impact of OCT1 polymorphism on the pharmacokinetics of morphine, 4 , 9 , 10 , 11 though data are not consistent. 12 , 13 …”