Clinical Pharmacology and Therapeutics

The Centre of Regulatory Excellence (CoRE) launched an annual lecture series in 2021 in Singapore to honor the memory of the late Professor Sir Alasdair Breckenridge, CoRE's founding Chair, and foster dialogue on global biomedical and regulatory perspectives, challenges, and advances. The 2022 Sir Alasdair Breckenridge Lecture "Success and Opportunities in the Pandemic" was delivered by Dr Penny M Heaton, former CEO of the Bill & Melinda Gates Foundation Research Institute and current Global Therapeutics Lead for Vaccines at Johnson & Johnson...

Mercaptopurine is a cornerstone of maintenance chemotherapy in childhood acute lymphoblastic leukemia (ALL). Its cytotoxic effects are mediated by 6-thioguanine nucleotides (TGN) incorporation into lymphocyte DNA. Thiopurine methyltransferase (TPMT) inactivates mercaptopurine, and deficiency resulting from genetic variants increases TGN exposure and hematopoietic toxicity. While mercaptopurine-dose reduction reduces toxicity risk without compromising relapse rate in patients with TPMT deficiency, dosing recommendations for those with moderately reduced activity (intermediate metabolizer, IM) are less clear and their clinical impacts have yet to be established...

No abstract text is available yet for this article.

No abstract text is available yet for this article.

Oral formulations prepared from the leaves of the kratom (Mitragyna speciosa) plant are increasingly used for their opioid-like effects to self-manage opioid withdrawal and pain. Calls to US poison centers involving kratom exposures increased >50-fold from 2011-2017, one-third of which reported concomitant use of kratom with drugs of abuse. Many of these drugs are eliminated primarily via cytochrome P450 (CYP) 3A and CYP2D6, raising concerns for potential adverse pharmacokinetic kratom-drug interactions...

Over 20% of Food and Drug Administration (FDA)-approved drugs in the United States are metabolized by the hepatic enzyme cytochrome P450 2D6 (CYP2D6). The gene encoding CYP2D6 is highly polymorphic and genetic variation has been shown to impact drug response for many commonly dispensed drugs including opioids and antidepressants. Thus, it is important to understand an individual's CYP2D6 metabolizer status to optimize treatment outcomes for patients taking medications that are metabolized by this enzyme. Consequently, clinical CYP2D6 pharmacogenetic testing is being implemented by a growing number of health centers...

Acetaminophen is commonly taken in overdose and can cause acute liver injury via the toxic metabolite NAPQI formed by cytochrome (CYP) P450 pathway. We aimed to evaluate the concentrations of acetaminophen metabolites on presentation following an acute acetaminophen poisoning and whether these predicted the subsequent onset of hepatotoxicity (peak ALT >1000 U/L). The Australian Toxicology Monitoring (ATOM) study is a prospective observational study, recruiting via two PICs and four toxicology units. Patients following an acute acetaminophen ingestion presenting <24h post-ingestion were recruited...

Primary human hepatocytes (PHHs) have been the gold standard in vitro model for the human liver and are crucial to predict hepatic drug-drug interactions. The aim of this work was to assess the utility of 3D spheroid PHHs to study induction of important cytochrome P450 (CYP) enzymes and drug transporters. 3D spheroid PHHs from three different donors were treated for four days with rifampicin, dicloxacillin, flucloxacillin, phenobarbital, carbamazepine, efavirenz, omeprazole or β-naphthoflavone. Induction of CYP1A1, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and transporters P-glycoprotein (P-gp)/ABCB1, multidrug resistance-associated protein 2 (MRP2)/ABCC2, ABCG2, organic cation transporter 1 (OCT1)/SLC22A1, SLC22A7, SLCO1B1 and SLCO1B3 were evaluated at mRNA and protein levels...

Sodium-glucose co-transporter 2 (SGLT2) inhibitors, including canagliflozin, reduce the risk of cardiovascular and kidney outcomes in patients with and without type 2 diabetes, albeit with a large inter-individual variation. The underlying mechanisms for this variation in response might be attributed to differences in SGLT2 occupancy, resulting from individual variation in plasma and tissue drug exposure and receptor availability. We performed a feasibility study for the use of [18 F]Canagliflozin positron emission tomography (PET) imaging to determine the association between clinical canagliflozin doses and SGLT2 occupancy in patients with type 2 diabetes...

Generating evidence from real-world data (RWD) requires fit-for-purpose study design and data. In addition to validity, decision makers require transparency in the reasoning that underlies study design and data source decisions. The 2019 Structured Preapproval and Postapproval Comparative study design framework to generate valid and transparent real-world Evidence (SPACE) and the 2021 Structured Process to Identify Fit-For-Purpose Data (SPIFD) - intended to be used together - provide a step-by-step guide to identify decision grade, fit-for-purpose study design and data...

To protect people from SARS-CoV-2 infection, tremendous research efforts have been made toward coronavirus disease 19 (COVID-19) treatments development. Externally controlled trial (ECT) may help reduce their development time. To evaluate whether ECT using real-world data (RWD) of COVID-19 patients is feasible enough to be used for regulatory decision-making, we built an external control arm (ECA) based on RWD as a control arm of a previously conducted randomized controlled trial (RCT), and compare it to the control arm of the RCT...

Direct oral anticoagulants (DOACs) have increasingly replaced warfarin for treating patients with non-valvular atrial fibrillation (NVAF). DOACs have been demonstrated to be more useful than warfarin, which was highlighted at its ethnic differences in efficacy and safety; however, the regional differences of DOACs remain unclear. We conducted a systematic review, meta-analysis, and meta-regression to evaluate the efficacy and safety of DOACs in patients from Asian and non-Asian regions with NVAF. We systematically searched randomized control trials published before August 2019...

Metformin is the first-line drug for type 2 diabetes (T2D) whilst acarbose is suggested as a viable alternative in Chinese patients with newly diagnosed T2D. However, little biomarkers had been established to guide the choice between these two agents. mtDNA copy number (mtDNA-CN) is a biomarker of mitochondrial function, which was associated with various metabolic outcomes. Using data from the trial of Metformin (n = 214) and AcaRbose (n = 198) in Chinese as the initial Hypoglycaemic treatment (MARCH), we examined whether mtDNA-CN was associated with response to the drugs in terms of glycaemic response and β-cell function protection response...

No abstract text is available yet for this article.

No abstract text is available yet for this article.

Donanemab is an amyloid-targeting therapy that resulted in robust amyloid plaque reduction and slowed Alzheimer's disease (AD) progression compared to placebo in the phase 2 TRAILBLAZER-ALZ study (NCT03367403). The objectives of the current analyses are to characterize (i) the population pharmacokinetics of donanemab, (ii) the relationship between donanemab exposure and amyloid plaque reduction (response), and (iii) the relationship between donanemab exposure and amyloid-related imaging abnormalities with edema or effusions (ARIA-E)...

Disease progression modeling (DPM) represents an important model-informed drug development framework. The scientific communities support the use of DPM to accelerate and increase efficiency in drug development. This article summarizes International Consortium for Innovation & Quality (IQ) in Pharmaceutical Development mediated survey activities conducted across multiple biopharmaceutical companies on challenges and opportunities for DPM. Additionally, this summary highlights the viewpoints of IQ from the workshop hosted by the FDA...

Clinical trials have demonstrated the benefit of PD-1/L1 blocking antibodies for the treatment of patients with advanced non-small cell lung cancer (NSCLC) in defined patient populations that often exclude patients with moderate or severe hepatic or renal impairment. We assessed the association between overall survival (OS) and baseline organ function in patients with advanced NSCLC treated with PD-1/L1 blocking antibodies in real-world data (RWD; patient-level data from electronic-health records) and pooled clinical trials data submitted to the FDA...

Warfarin is extensively metabolized by cytochrome P450 2C9 (CYP2C9). Concomitant use with the potent CYP2C9 inducer, rifampin, requires close monitoring and dosage adjustments. While, in theory, warfarin dose increase should overcome this interaction, most reported cases over the last fifty years have not responded even to high warfarin doses, but some have responded to modest doses. To investigate the genetic polymorphisms' impact on this unexplained interpatient variability, we performed genotyping of CYP2C9, VKORC1, and CYP4F2 for warfarin and rifampin concomitant receivers from 2016 to 2022 at Hamad Medical Corporation, Doha, Qatar...

Despite (repeated) boostering, kidney transplant recipients (KTR) may remain at increased risk of severe COVID-19 since a substantial amount of individuals remain seronegative or with low antibody titers. In particular, mycophenolic acid (MPA) use has been shown to affect antibody formation negatively and may be an important modifiable risk factor. We investigated the exposure-response relationship between MPA area-under-the-curve0-12h (AUC0-12h ) exposure and seroconversion including antibody titers after vaccination using mRNA-1273 SARS-CoV-2 vaccine (Moderna) in 316 KTR from our center that participated in the national Dutch RECOVAC LESS CoV-2 vaccination study...