Adapting regulatory drug‐drug interaction guidance to design clinical pharmacokinetic natural product‐drug interaction studies: A NaPDI Center recommended approach

Pharmacokinetic drug interactions precipitated by botanical and other natural products (NPs) remain critically understudied. Investigating these complex interactions is fraught with difficulties due to the methodologic and technical challenges associated with the inherently complex chemistries and product variability of NPs. This knowledge gap is perpetuated by a continuing absence of a harmonized framework regarding the design of clinical pharmacokinetic studies of NPs and NP‐drug interactions. Accordingly, this Recommended Approach, the fourth in a series of Recommended Approaches released by the Center of Excellence for Natural Product Drug Interaction Research (NaPDI Center), provides recommendations for the design of clinical pharmacokinetic studies involving NPs. Building on prior Recommended Approaches and data generated from the NaPDI Center, such a framework is presented for the design of (1) phase 0 studies to assess the pharmacokinetics of an NP and (2) clinical pharmacokinetic NP‐drug interaction studies. Suggestions for NP sourcing, dosing, study design, participant selection, sampling periods, and data analysis are presented. With the intent to begin addressing the gap between regulatory agencies’ guidance documents about drug‐drug interactions and contemporary NPDI research, the objective of this Recommended Approach is to propose methods for the design of clinical pharmacokinetic studies of NPs and NP‐drug interactions.     

Defining and Optimizing Value in Total Joint Arthroplasty From the Patient,Payer, and Provider Perspectives

BackgroundThe purpose of this study is to define value in bundled total joint arthroplasty (TJA) from the differing perspectives of the patient, payer/employer, and hospital/provider.MethodsDemographic, psychosocial, clinical, financial, and patient-reported outcomes (PROs) data from 2017 to 2018 elective TJA cases at a multihospital academic health system were queried. Value was defined as improvement in PROs (preoperatively to 1 year postoperatively) for patients, improvement in PROs per $1000 of bundle cost for payers, and the normalized sum of improvement in PROs and hospital bundle margin for providers. Bivariate analysis was used to compare high value vs low value (>50th percentile vs <50th percentile). Multivariate analysis was performed to identify predictors.ResultsA total of 280 patients had PRO data, of which 71 had Medicare claims data. Diabetes (odds ratio [OR], 0.45; P = .02) predicted low value for patients; female gender (OR, 0.25), hypertension (OR, 0.17), pulmonary disease (OR, 0.12), and skilled nursing facility discharge (OR, 0.17) for payers (P ≤ .03 for all); and pulmonary disease (OR, 0.16) and skilled nursing facility discharge (OR, 0.19) for providers (P ≤ .04 for all).ConclusionThis is the first article to define value in TJA under a bundle payment model from multiple perspectives, providing a foundation for future studies analyzing value-based TJA.     

Role of the Breast Cancer Resistance Protein (BCRP/ABCG2) in Drug Transport—an Update

The human breast cancer resistance protein (BCRP, gene symbol ABCG2) is an ATP-binding cassette (ABC) efflux transporter. It was so named because it was initially cloned from a multidrug-resistant breast cancer cell line where it was found to confer resistance to chemotherapeutic agents such as mitoxantrone and topotecan. Since its discovery in 1998, the substrates of BCRP have been rapidly expanding to include not only therapeutic agents but also physiological substances such as estrone-3-sulfate, 17β-estradiol 17-(β-d-glucuronide) and uric acid. Likewise, at least hundreds of BCRP inhibitors have been identified. Among normal human tissues, BCRP is highly expressed on the apical membranes of the placental syncytiotrophoblasts, the intestinal epithelium, the liver hepatocytes, the endothelial cells of brain microvessels, and the renal proximal tubular cells, contributing to the absorption, distribution, and elimination of drugs and endogenous compounds as well as tissue protection against xenobiotic exposure. As a result, BCRP has now been recognized by the FDA to be one of the key drug transporters involved in clinically relevant drug disposition. We published a highly-accessed review article on BCRP in 2005, and much progress has been made since then. In this review, we provide an update of current knowledge on basic biochemistry and pharmacological functions of BCRP as well as its relevance to drug resistance and drug disposition.KEY WORDS: ABCG2, ATP-binding cassette, BCRP, drug transport, transporter     

Does centralisation of acute obstetric care reduce intrapartum and first-week mortality? An empirical study of over 1 million births in the Netherlands

In this hypothetical analysis with retrospective cohort data (1,160,708 hospital births) we estimated outcome of centralisation of acute obstetric care, i.e., closure of 10 hospitals (out of 99) in The Netherlands. The main outcome was predicted intrapartum and first-week mortality (further referred to as neonatal mortality) for several subgroups of patients affected by two centralisation scenarios: (1) closure of the 10 smallest hospitals; (2) closure of the 10 smallest hospitals, but avoiding adjacent closures. Predictions followed from regression coefficients from a multilevel logistic regression model. Scenario 1 resulted in doubled travel time, and 10% increased mortality (210 [0.34%] to 231 [0.38%] cases). Scenario 2 showed less effect on mortality (268 [0.33%] to 259 [0.32%] cases) and travel time. Heterogeneity in hospital organisational features caused simultaneous improvement and deterioration of predicted neonatal mortality. Consequences vary for subgroups. We demonstrate that (in The Netherlands) centralisation of acute obstetric care according to the ‘closure-of-the-smallest-rule’ yields suboptimal outcomes. In order to develop an optimal strategy one would need to consider all positive and negative effects, e.g., organisational heterogeneity of closing and surviving hospitals, differential effects for patient subgroups, increased travel time, and financial aspects. The provided framework may be beneficial for other countries considering centralisation of acute obstetric care.     

Optimized Approaches for Quantification of Drug Transporters in Tissues and Cells by MRM Proteomics

Drug transporter expression in tissues (in vivo) usually differs from that in cell lines used to measure transporter activity (in vitro). Therefore, quantification of transporter expression in tissues and cell lines is important to develop scaling factor for in vitro to in vivo extrapolation (IVIVE) of transporter-mediated drug disposition. Since traditional immunoquantification methods are semiquantitative, targeted proteomics is now emerging as a superior method to quantify proteins, including membrane transporters. This superiority is derived from the selectivity, precision, accuracy, and speed of analysis by liquid chromatography tandem mass spectrometry (LC-MS/MS) in multiple reaction monitoring (MRM) mode. Moreover, LC-MS/MS proteomics has broader applicability because it does not require selective antibodies for individual proteins. There are a number of recent research and review papers that discuss the use of LC-MS/MS for transporter quantification. Here, we have compiled from the literature various elements of MRM proteomics to provide a comprehensive systematic strategy to quantify drug transporters. This review emphasizes practical aspects and challenges in surrogate peptide selection, peptide qualification, peptide synthesis and characterization, membrane protein isolation, protein digestion, sample preparation, LC-MS/MS parameter optimization, method validation, and sample analysis. In particular, bioinformatic tools used in method development and sample analysis are discussed in detail. Various pre-analytical and analytical sources of variability that should be considered during transporter quantification are highlighted. All these steps are illustrated using P-glycoprotein (P-gp) as a case example. Greater use of quantitative transporter proteomics will lead to a better understanding of the role of drug transporters in drug disposition.