Oxymorphone Active Uptake at the Blood–Brain Barrier and Population Modeling of its Pharmacokinetic–Pharmacodynamic Relationship

Sadiq, Muhammad Waqas; Boström, Emma; Keizer, Ron J.; Björkman, Sven; Hammarlund‐Udenaes, Margareta

doi:10.1002/jps.23492

Cited by 30 publications

(20 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A log likelihood approach to model right censored data as proposed by Sadiq et al [28] was attempted but did not allow successful modelling with Phoenix NLME. In addition, PD modelling has not been described for norbuprenorphine in cats.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic and pharmacodynamic modelling after subcutaneous, intravenous and buccal administration of a high-concentration formulation of buprenorphine in conscious cats

et al. 2017

View full text Add to dashboard Cite

BackgroundThe aim of this study was to describe the joint pharmacokinetic-pharmacodynamic model and evaluate thermal antinociception of a high-concentration formulation of buprenorphine (Simbadol™) in cats.MethodsSix healthy cats (4.9 ± 0.7 kg) were included in a prospective, randomized, blinded, crossover study. Simbadol™ (1.8 mg mL-1) was administered by the subcutaneous (SC; 0.24 mg kg-1), intravenous (IV; 0.12 mg kg-1) or buccal (OTM; 0.12 mg kg-1) route of administration and thermal thresholds (TT) were compared with a saline group (SAL). Thermal threshold testing and blood sampling were performed at predetermined time points up to 72 hours including a placebo group. Plasma buprenorphine and norbuprenorphine concentrations were measured using liquid chromatography mass spectrometry. A bespoke bicompartmental pharmacokinetic model simultaneously fitted data from two analytes/three routes of administration. Temporal changes in TT were analyzed using one-way ANOVA followed by Dunnett’s test and treatment comparisons using two-way ANOVA with Bonferroni’s correction (P < 0.05).ResultsThermal thresholds were significantly increased after SC, IV and OTM from 1–24 hours (except 2 hours), 0.5–8 hours (except 6 hours), and 1–8 hours (except 6 hours), respectively, when compared with baseline. Thermal thresholds were significantly increased after SC (1–30 hours), IV (1–8 hours) and OTM (1–12 hours) when compared with SAL, but not different among buprenorphine-treated cats. The absolute buprenorphine clearance was 0.98 L kg-1 hour-1, volume of distribution at steady state was 7.9 L kg-1 and the elimination-half-life was 12.3 hours. Bioavailability for SC and OTM was 94% and 24%, respectively. Subcutaneous absorption was biphasic. An initial peak (0.08 hours) was followed by a slow (half-life 11.2 hours) and progressive (peak acceleration at 2.8 hours) uptake.ConclusionThe SC administration of Simbadol™ was characterized by prolonged absorption half-life and sustained plasma concentrations yielding long-lasting antinociception (≥ 24 hours) when compared with the IV and OTM routes.

show abstract

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic and pharmacodynamic modelling after subcutaneous, intravenous and buccal administration of a high-concentration formulation of buprenorphine in conscious cats

et al. 2017

View full text Add to dashboard Cite

show abstract

“…However, such studies are still sparse and require state-of-the-art analytical equipment (4,5). Modeling, being an important part in systems pharmacology analysis, has been used rather extensively in microdialysis studies to refine the raw data and interpret the findings (1)(2)(3)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

Microdialysis as an Important Technique in Systems Pharmacology—a Historical and Methodological Review

Hammarlund‐Udenaes

2017

AAPS J

Self Cite

View full text Add to dashboard Cite

Abstract.Microdialysis has contributed with very important knowledge to the understanding of target-specific concentrations and their relationship to pharmacodynamic effects from a systems pharmacology perspective, aiding in the global understanding of drug effects. This review focuses on the historical development of microdialysis as a method to quantify the pharmacologically very important unbound tissue concentrations and of recent findings relating to modeling microdialysis data to extrapolate from rodents to humans, understanding distribution of drugs in different tissues and disease conditions. Quantitative microdialysis developed very rapidly during the early 1990s. Method development was in focus in the early years including development of quantitative microdialysis, to be able to estimate true extracellular concentrations. Microdialysis has significantly contributed to the understanding of active transport at the blood-brain barrier and in other organs. Examples are presented where microdialysis together with modeling has increased the knowledge on tissue distribution between species, in overweight patients and in tumors, and in metabolite contribution to drug effects. More integrated metabolomic studies are still sparse within the microdialysis field, although a great potential for tissue and disease-specific measurements is evident.

show abstract

“…One in vitro study demonstrated that oxymorphone does not significantly stimulate P-gp ATPase activity (111), while a rat study demonstrated active transport is involved in the BBB uptake of oxymorphone through an unidentified transporter (125). Due to the limited transporter information available, it is not possible to predict potential transporter-mediated DDIs for oxymorphone without further studies.…”

Section: Oxymorphonementioning

confidence: 99%

“…GLUTs have established roles as glucose and/or fructose transporters, but their other major substrates have likely not yet been identified, making predicting potential transporter-mediated DDIs difficult (246). There also appear to be unidentified active transporters involved in the BBB transport of oxymorphone (125) and fentanyl (126). Other active transporters which have yet to be fully elucidated include the probenecid-like transporter of M6G (putative OAT) (57), the digoxin-sensitive BBB transporter (putative OATP1B1) (56) of morphine, and pyrilamine BBB transporter of oxycodone (putative OCT) (121).…”

Section: Other Emerging Bbb Transportersmentioning

confidence: 99%

Transporter-Mediated Disposition of Opioids: Implications for Clinical Drug Interactions

et al. 2015

View full text Add to dashboard Cite

Opioid-related deaths, abuse, and drug interactions are growing epidemic problems that have medical, social, and economic implications. Drug transporters play a major role in the disposition of many drugs, including opioids; hence they can modulate their pharmacokinetics, pharmacodynamics and their associated drug-drug interactions (DDIs). Our understanding of the interaction of transporters with many therapeutic agents is improving; however, investigating such interactions with opioids is progressing relatively slowly despite the alarming number of opioids-mediated DDIs that may be related to transporters. This review presents a comprehensive report of the current literature relating to opioids and their drug transporter interactions. Additionally, it highlights the emergence of transporters that are yet to be fully identified but may play prominent roles in the disposition of opioids, the growing interest in transporter genomics for opioids, and the potential implications of opioid-drug transporter interactions for cancer treatments. A better understanding of drug transporters interactions with opioids will provide greater insight into potential clinical DDIs and could help improve opioids safety and efficacy.

show abstract

Oxymorphone Active Uptake at the Blood–Brain Barrier and Population Modeling of its Pharmacokinetic–Pharmacodynamic Relationship

Cited by 30 publications

References 39 publications

Pharmacokinetic and pharmacodynamic modelling after subcutaneous, intravenous and buccal administration of a high-concentration formulation of buprenorphine in conscious cats

Pharmacokinetic and pharmacodynamic modelling after subcutaneous, intravenous and buccal administration of a high-concentration formulation of buprenorphine in conscious cats

Microdialysis as an Important Technique in Systems Pharmacology—a Historical and Methodological Review

Transporter-Mediated Disposition of Opioids: Implications for Clinical Drug Interactions

Contact Info

Product

Resources

About