We successfully developed and validated a rapid, sensitive and robust UPLC-MS/MS assay with simple sample preparation to quantify the concentration of buprenorphine, norbuprenorphine, buprenorphine glucuronide and norbuprenorphine glucuronide in human plasma. The advantages of this analytical method include simple sample processing, small plasma volume requirement, high recovery of BUP and three of its metabolites, and short sample run time. We applied the assay to evaluate the pharmacokinetics of buprenorphine and its three metabolites in pregnant women.
This assay enables us to quantify concentration time profiles of buprenorphine, norbuprenorphine, buprenorphine glucuronide and norbuprenorphine glucuronide after low dose of BUP using limited volume of blood samples.
A Physiologically Based Pharmacokinetic Modeling Approach to Predict Buprenorphine Pharmacokinetics following Intravenous & Sublingual Administration
(This chapter has been published in the British Journal Clinical Pharmacology (2017) 83: 2458–2473)
3.1 Abstract
Introduction: Opioid dependence is associated with high morbidity and mortality.
Buprenorphine (BUP) is approved by the FDA to treat opioid dependence. There is a lack of clear consensus on the appropriate dosing of BUP in the presence of inter-patient physiological differences in absorption/disposition, subjective response assessment and other patient comorbidities. The objective of this study is to build and validate robust physiologically-based-pharmacokinetic (PBPK) models for intravenous (IV) and sublingual (SL) BUP in non-pregnant adults as a first step to optimize BUP pharmacotherapy.
Methods: BUP-PBPK modeling and simulations were performed using Simcyp® by incorporating physiochemical properties of BUP, establishing Inter-System Extrapolation Factors (ISEF) based In-Vitro In-Vivo Extrapolation (IVIVE) methods to extrapolate in-vitro enzyme activity data, and using tissue specific Kp estimations. Published data on IV and SL BUP in opioid and non-opioid dependent patients was used to build the models. Fourteen model naïve BUP-PK datasets were used for inter-study and intra-study validations.
Results: IV and SL BUP-PBPK models developed are robust in predicting multi-compartment disposition of BUP over a dosing range of 0.3-32 mg. Predicted plasma concentration-time profiles in virtual patients are consistent with reported data across 5 IV-single dose studies, 5 SL-single dose studies and 4 SL-multiple dose studies. All PK parameter predictions were within 75%-137% of the corresponding observed data. The model developed predicted brain concentration of BUP to be about 4 times higher than that of BUP in plasma.
Conclusion: The validated PBPK models will be used in future studies to predict BUP plasma and brain concentrations based on varying demographic, physiological and pathological characteristics of the patients.
3.2 Introduction
Drug overdose and associated deaths have become a nation-wide crisis in the United States [240]. Data from the Centers for Disease Control and Prevention (CDC) indicate that deaths associated with drug overdose are predominantly driven by an increase in opioid abuse [241-243].
Broadly speaking, the term opioid applies to any endogenous or exogenous substance that interacts with the opioid receptors present in the body [244]. Because of their efficacy in pain management, prescription opioids, such as morphine, hydromorphone, oxycodone, hydrocodone and fentanyl are routinely used in patients [245]. Besides blocking pain-signaling pathway, opiates also activate brain reward system and produce euphoric effects. This makes them highly addictive with prolonged exposure [246, 247].
Opioid dependence is associated with high morbidity and mortality [248, 249]. There is no cure for opioid dependence. Medication-assisted maintenance therapies can reduce complications of opioid dependence, as a consequence of decreased illicit drug use [250, 251]. Currently methadone, buprenorphine (BUP), and naltrexone are the three primary pharmacotherapies approved for treating opioid dependence. The effectiveness of methadone as a maintenance treatment for opioid dependence has been demonstrated in many clinical studies [252, 253]. As a full mu receptor agonist, methadone has abuse potential; consequently methadone maintenance treatment requires daily patient clinic visits. Naltrexone is a mu receptor antagonist; it can reduce illicit drug use by blocking euphoric effects and has no abuse potential, but poor patient retention hampers its routine clinical use [254, 255].
The Food and Drug Administration (FDA) approved BUP for treatment of opioid addiction in 2002. Compared to methadone, BUP is a relatively new drug that has several advantages in clinical practice. BUP exhibits mixed agonist-antagonist opioid effect [256, 257], is highly potent towards kappa (antagonist) and mu (partial agonist) opioid receptors; and it is roughly 50-100 times more potent than morphine [258]. BUP has a ceiling dose-response profile, which limits the risk of major life-threatening adverse effects associated with mu receptor agonists such as respiratory depression [259]. Because of this profile, BUP can provide competitive antagonism to other illicit opioids. In recent times, a sublingual (SL) formulation of BUP (Subutex®) has been shown to be more favorable due to its safety profiles and ease of administration [260]. Suboxone®, a SL BUP formulation in combination with naloxone (full mu receptor antagonist), is another product which was developed and approved to avoid intravenous (IV) abuse.
Despite the proven efficacy of BUP in treating opioid addiction, a meta-analysis showed that patients on BUP had 1.26 times relative risk of discontinuing the treatment compared to patients receiving methadone [261]. In addition, a randomized phase IV study found BUP to be associated with 54% of patient dropout compared to 26% in the methadone group [262]. Several factors such as lack of clear consensus on induction and a maintenance dosing regimen for BUP;
subjectivity of the of the Clinical Opioid Withdrawal (COW) scale that is used to determine the dose [263]; confounding effects of factors such as mental health comorbidities, smoking, as well as concomitant medication use that can confound COW scoring and selection of improper BUP dosing would have an impact on the outcomes of BUP therapy and in turn affect compliance. In addition, there is a high inter-patient variability in the bioavailability of BUP due to differences in the extent of absorption with sublingual administration in different patients [264].
A better understanding of the physiological and drug formulation parameters affecting BUP pharmacokinetic and pharmacodynamic profiles is needed to develop a more objective dosing regimen of BUP. Physiologically based pharmacokinetic (PBPK) modeling is a very comprehensive and relatively inexpensive strategy to address the impact of various clinical pharmacotherapeutic factors that impact drug dosing. PBPK modeling approach incorporates a drug’s physiochemical properties, human physiological variables and population variability estimates to predict drug exposure [265]. Because PBPK models incorporate anatomical, physiological, and metabolic attributes, any physiological alterations induced by disease, age, gender, genetic polymorphism, and other pathophysiologic conditions can be captured by such models. To the best of our knowledge, the use of PBPK modeling in predicting BUP exposure has not been explored in adult populations. The objective of this study is to predict the time courses of BUP following IV and SL administration of BUP in an attempt to optimize dosing of BUP in patients through the development of BUP PBPK models.