Cancer Cachexia Raises the Plasma Concentration of Oxymorphone Through the Reduction of CYP3A But Not CYP2D6 in Oxycodone-Treated Patients

Naito, Takafumi; Tashiro, Masaki; Ishida, Takuya; Ohnishi, Kazunori; Kawakami, Junichi

doi:10.1002/jcph.112

Cited by 24 publications

(19 citation statements)

References 25 publications

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“…Cachectic patients (BMI of Ͻ18.5 kg/m 2 ) have decreased plasma and liver volumes and reduced levels of CYP3A4 and other cytochromes, resulting in attenuated ISA metabolism (19). Drug clearance (CL) might also be reduced in cachectic patients (19)(20)(21). Indeed, CL among our patients with a BMI of Ͻ18.5 kg/m 2 was lower than that in patients with a BMI of Ն18.5 kg/m 2 (2.0 liters/h versus 3.9 liters/h; P ϭ 0.02).…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of Intravenous Isavuconazole in Solid-Organ Transplant Recipients

Clancy

Rivosecchi

et al. 2018

Antimicrob Agents Chemother

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Isavuconazole may be useful in treating and preventing fungal infections in solid-organ transplant (SOT) recipients due to its safety profile and activity against Aspergillus and some Mucorales. Isavuconazole has favorable pharmacokinetics based on clinical trials in various patient populations, but data are limited in SOT recipients. We evaluated the steady-state pharmacokinetics of isavuconazole in 26 SOT recipients receiving the drug intravenously for prophylaxis. There was moderate interpatient variability in isavuconazole pharmacokinetic parameters (coefficients of variation of 51% for the area under the plasma concentration-versus-time curve [AUC] and 59% for the trough plasma concentration [C trough ]). AUC and steady-state C trough were significantly lower in women, patients with a body mass index of Ն18.5 kg/m 2 , and those receiving hemodialysis. Trough plasma concentrations were highly correlated with AUCs (R 2 ϭ 0.94) and can serve as a suitable measure of isavuconazole exposure in patients. In conclusion, moderate interpatient variability in isavuconazole exposure, the identification of factors associated with lower exposure, the recognition that C trough is a surrogate marker for AUC, and the availability of a simple analytical method suggest that therapeutic drug monitoring (TDM) may be useful for guiding treatment in at least some SOT recipients. Future studies are needed to correlate isavuconazole exposure with patients' clinical outcomes and to determine the clinical role of TDM.

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Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of Intravenous Isavuconazole in Solid-Organ Transplant Recipients

Clancy

Rivosecchi

et al. 2018

Antimicrob Agents Chemother

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“…Cachectic patients experience a decrease in CYP3A enzymatic activity but no major change in CYP2D6 activity. This results in lower plasma concentrations of the main metabolite noroxycodone, and increased oxycodone and oxymorphone exposure [111][112][113][114]. Cachexia is also characterised by hypoalbuminemia [115].…”

Section: Cancer Pain and Cachexic Patientsmentioning

confidence: 99%

Updated Clinical Pharmacokinetics and Pharmacodynamics of Oxycodone

et al. 2019

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Global oxycodone consumption has increased sharply during the last two decades, and, in 2008, oxycodone consumption surpassed that of morphine. As oxycodone was synthesized in 1916 and taken to clinical use a year later, it has not undergone the same approval process required by today's standards. Most of the basic oxycodone pharmacokinetic (PK) data are from the 1990s and from academic research; however, a lot of additional data have been published over the last 10 years. In this review, we describe the latest oxycodone data on special populations, including neonates, children, pregnant and lactating women, and the elderly. A lot of important drug interaction data have been published that must also be taken into account when oxycodone is used concomitantly with cytochrome P450 (CYP) 3A inducers and inhibitors and/or CYP2D6 inhibitors. In addition, we gathered data on abuse-deterrent oxycodone formulations, and the PK of alternate administration routes, i.e. transmucosal and epidural, are also described. Mari Kinnunen and Panu Piirainen contributed equally to this work.

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“…Approximately, 99% of oxycodone is distributed outside the plasma compartment, as reflected by the large volume of distribution of oxycodone (2-3 L/kg). The main known metabolic pathways of oxycodone are through O-demethylation to oxymorphone via CYP2D6 and through N-demethylation to noroxycodone via CYP 3A4 (Lalovic et al 2006;Gronlund et al 2011;Naito et al 2013;Soderberg Lofdal et al 2013). Oxycodone itself is the major contributor to the analgesic effect fol-lowing oxycodone administration.…”

Section: Introductionmentioning

confidence: 99%

Slow drug delivery decreased total body clearance and altered bioavailability of immediate‐ and controlled‐release oxycodone formulations

Li¹,

Sun

Palmisano³

et al. 2016

Pharmacology Res & Perspec

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Oxycodone is a commonly used analgesic with a large body of pharmacokinetic data from various immediate‐release or controlled‐release formulations, under different administration routes, and in diverse populations. Longer terminal half‐lives from extravascular administration as compared to IV administration have been attributed to flip‐flop pharmacokinetics with the rate constant of absorption slower than elimination. However, PK parameters from the extravascular studies showed faster absorption than elimination. Sustained release formulations guided by the flip‐flop concept produced mixed outcomes in formulation development and clinical studies. This research aims to develop a mechanistic knowledge of oxycodone ADME, and provide a consistent interpretation of diverging results and insight to guide further extended release development and optimize the clinical use of oxycodone. PK data of oxycodone in human studies were collected from literature and digitized. The PK data were analyzed using a new PK model with Weibull function to describe time‐varying drug releases/ oral absorption, and elimination dependent upon drug input to the portal vein. The new and traditional PK models were coded in NONMEM. Sensitivity analyses were conducted to address the relationship between rates of drug release/absorption and PK profiles plus terminal half‐lives. Traditional PK model could not be applied consistently to describe drug absorption and elimination of oxycodone. Errors were forced on absorption, elimination, or both parameters when IV and PO profiles were fitted separately. The new mechanistic PK model with Weibull function on absorption and slower total body clearance caused by slower absorption adequately describes the complex interplay between oxycodone absorption and elimination in vivo. Terminal phase of oxycodone PK profile was shown to reflect slower total body drug clearance due to slower drug release/absorption from oral formulations. Mechanistic PK models with Weibull absorption functions, and release rate‐dependent saturable total body clearance well described the diverging oxycodone absorption and elimination kinetics in the literature. It showed no actual drug absorption during the terminal phase, but slower drug clearance caused by slower release/absorption producing the appearance of flip‐flop and offered new insight for the development of modified release formulations and clinical use of oxycodone.

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Cancer Cachexia Raises the Plasma Concentration of Oxymorphone Through the Reduction of CYP3A But Not CYP2D6 in Oxycodone-Treated Patients

Cited by 24 publications

References 25 publications

Pharmacokinetics of Intravenous Isavuconazole in Solid-Organ Transplant Recipients

Pharmacokinetics of Intravenous Isavuconazole in Solid-Organ Transplant Recipients

Updated Clinical Pharmacokinetics and Pharmacodynamics of Oxycodone

Slow drug delivery decreased total body clearance and altered bioavailability of immediate‐ and controlled‐release oxycodone formulations

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