Concurrent Assessment of Hepatic and Intestinal Cytochrome P450 3A Activities Using Deuterated Alfentanil

Kharasch, Evan D.; Vangveravong, Suwanna; Buck, Nikki; London, Amy; Kim, Thomas; Blood, Jane; Mach, Robert H.

doi:10.1038/clpt.2010.313

Cited by 14 publications

(10 citation statements)

References 44 publications

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“…A higher noroxycodone/oxycodone ratio and a higher daily oxycodone escalation rate was described in cancer patients carrying the CYP3A5*3/*3 genotype [9], however, an association of plasma concentrations and analgesic consumption to CYP3A5 genotype could not be confirmed in the present trial. It is well described that comedication with voriconazole, itraconazole, telithromycin, rifampin or ketoconazol produces considerable changes in oxycodone's pharmacokinetic [2], [3], [29]–[33] and even foods like grapefruit juice can inhibit CYP3A activity with respective interactions [34]. Several authors have pointed out that dose adjustment of oxycodone might be necessary, when used concomitantly with CYP inducers or inhibitors to either maintain adequate analgesia or prevent overdosing [31], [32].…”

Section: Discussionmentioning

confidence: 99%

CYP2D6 Genotype Dependent Oxycodone Metabolism in Postoperative Patients

et al. 2013

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BackgroundThe impact of polymorphic cytochrome P450 CYP2D6 enzyme on oxycodone's metabolism and clinical efficacy is currently being discussed. However, there are only spare data from postoperative settings. The hypothesis of this study is that genotype dependent CYP2D6 activity influences plasma concentrations of oxycodone and its metabolites and impacts analgesic consumption.MethodsPatients received oxycodone 0.05 mg/kg before emerging from anesthesia and patient-controlled analgesia (PCA) for the subsequent 48 postoperative hours. Blood samples were drawn at 30, 90 and 180 minutes after the initial oxycodone dose. Plasma concentrations of oxycodone and its metabolites oxymorphone, noroxycodone and noroxymorphone were analyzed by liquid chromatography-mass spectrometry with electrospray ionization. CYP2D6 genotyping was performed and 121 patients were allocated to the following genotype groups: PM (poor metabolizer: no functionally active CYP2D6 allele), HZ/IM (heterozygous subjects, intermediate metabolizers with decreased CYP2D6 activity), EM (extensive metabolizers, normal CYP2D6 activity) and UM (ultrarapid metabolizers, increased CYP2D6 activity). Primary endpoint was the genotype dependent metabolite ratio of plasma concentrations oxymorphone/oxycodone. Secondary endpoint was the genotype dependent analgesic consumption with calculation of equianalgesic doses compared to the standard non-CYP dependent opioid piritramide.ResultsMetabolism differed between CYP2D6 genotypes. Mean (95%-CI) oxymophone/oxycodone ratios were 0.10 (0.02/0.19), 0.13 (0.11/0.16), 0.18 (0.16/0.20) and 0.28 (0.07/0.49) in PM, HZ/IM, EM and UM, respectively (p = 0.005). Oxycodone consumption up to the 12th hour was highest in PM (p = 0.005), resulting in lowest equianalgesic doses of piritramide versus oxycodone for PM (1.6 (1.4/1.8); EM and UM 2.2 (2.1/2.3); p<0.001). Pain scores did not differ between genotypes.ConclusionsIn this postoperative setting, the number of functionally active CYP2D6 alleles had an impact on oxycodone metabolism. The genotype also impacted analgesic consumption, thereby causing variation of equianalgesic doses piritramide : oxycodone. Different analgesic needs by genotypes were met by PCA technology in this postoperative cohort.

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Section: Discussionmentioning

confidence: 99%

CYP2D6 Genotype Dependent Oxycodone Metabolism in Postoperative Patients

et al. 2013

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“…2; Table 3), which allows quantification of the difference in induction between intestine and liver. The influence of rifampicin on the CYP3A4 substrate alfentanil, a moderate clearance drug, showed that the fraction escaping the liver unchanged (F H ), measured after an intravenous dose of alfentanil, decreased from 0.74 in the control situation to 0.29 with rifampicin treatment (Kharasch et al, 2011). These investigators demonstrated that after oral administration of alfentanil, F G decreased from 0.68 to 0.19 with rifampicin administration, highlighting a similar change in intestinal and hepatic induction.…”

Section: Downloaded Frommentioning

confidence: 94%

Perspectives from the Innovation and Quality Consortium Induction Working Group on Factors Impacting Clinical Drug-Drug Interactions Resulting from Induction: Focus on Cytochrome 3A Substrates

Ramsden

Fung

Hariparsad

et al. 2019

Drug Metabolism and Disposition

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A recent publication from the Innovation and Quality Consortium Induction Working Group collated a large clinical data set with the goal of evaluating the accuracy of drug-drug interaction (DDI) prediction from in vitro data. Somewhat surprisingly, comparison across studies of the mean-or median-reported area under the curve ratio showed appreciable variability in the magnitude of outcome. This commentary explores the possible drivers of this range of outcomes observed in clinical induction studies. While recommendations on clinical study design are not being proposed, some key observations were informative during the aggregate analysis of clinical data. Although DDI data are often presented using median data, individual data would enable evaluation of how differences in study design, baseline expression, and the number of subjects contribute. Since variability in perpetrator pharmacokinetics (PK) could impact the overall DDI interpretation, should this be routinely captured? Maximal induction was typically observed after 5-7 days of dosing. Thus, when the half-life of the inducer is less than 30 hours, are there benefits to a more standardized study design? A large proportion of CYP3A4 inducers were also CYP3A4 inhibitors and/or inactivators based on in vitro data. In these cases, using CYP3A selective substrates has limitations. More intensive monitoring of changes in area under the curve over time is warranted. With selective CYP3A substrates, the net effect was often inhibition, whereas less selective substrates could discern induction through mechanisms not susceptible to inhibition. The latter included oral contraceptives, which raise concerns of reduced efficacy following induction. Alternative approaches for modeling induction, such as applying biomarkers and physiologically based pharmacokinetic modeling (PBPK), are also considered. SIGNIFICANCE STATEMENT The goal of this commentary is to stimulate discussion on whether there are opportunities to optimize clinical drug-drug interaction study design. The overall aim is to reduce, understand and contextualize the variability observed in the magnitude of induction across reported clinical studies. A large clinical CYP3A induction dataset was collected and further analyzed to identify trends and gaps. Reporting individual victim PK data, characterizing perpetrator PK and including additional PK assessments for mixed-mechanism perpetrators may provide insights into how these factors impact differences observed in clinical outcomes. The potential utility of biomarkers and PBPK modeling are discussed in considering future directions.

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“…ALF intravenous (i.v.) and oral clearances have been used to probe hepatic, intestinal, and first‐pass CYP3A activities 11 , 12 , 15 , 22 , 23 , 24 , 25 , 26 . In addition, single‐point ALF plasma concentrations have been used as a surrogate for ALF clearance, and to assess hepatic and first‐pass CYP3A activities 15 , 23 .…”

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confidence: 99%

Sensitivity of Intravenous and Oral Alfentanil and Pupillary Miosis as Minimal and Noninvasive Probes for Hepatic and First-Pass CYP3A Induction

Kharasch

Francis

London

et al. 2011

Clin Pharmacol Ther

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Systemic and oral clearances of alfentanil are in vivo probes for hepatic and first-pass CYP3A. Both alfentanil single point plasma concentrations and miosis are surrogates for area under the concentration-time curve (AUC), clearance, and are minimal and non-invasive CYP3A probes. This investigation determined alfentanil sensitivity for detecting graded CYP3A induction, and compared it with that of midazolam Twelve volunteers (sequential crossover) received 0, 5, 10, 25 or 75 mg oral rifampin for 5d. Midazolam and alfentanil were given intravenously and orally on sequential days. Dark-adapted pupil diameters were measured with blood sampling. Graded rifampin decreased plasma midazolam AUCs to 83, 76, 62 and 59% (intravenous) and 78, 66, 39, and 24% (oral) of control. Hepatic and first-pass CYP3A induction were detected comparably by plasma midazolam and alfentanil AUCs. Single alfentanil concentrations detected all CYP3A induction, while midazolam was less sensitive. Alfentanil miosis detected induction of first-pass but not hepatic CYP3A.

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Concurrent Assessment of Hepatic and Intestinal Cytochrome P450 3A Activities Using Deuterated Alfentanil

Cited by 14 publications

References 44 publications

CYP2D6 Genotype Dependent Oxycodone Metabolism in Postoperative Patients

CYP2D6 Genotype Dependent Oxycodone Metabolism in Postoperative Patients

Perspectives from the Innovation and Quality Consortium Induction Working Group on Factors Impacting Clinical Drug-Drug Interactions Resulting from Induction: Focus on Cytochrome 3A Substrates

Sensitivity of Intravenous and Oral Alfentanil and Pupillary Miosis as Minimal and Noninvasive Probes for Hepatic and First-Pass CYP3A Induction

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