Dorzagliatin is a first-in-class small molecule glucokinase activator (GKA) that improves pancreatic insulin secretion behavior and regulates hepatic glucose conversion in a glucose concentration-dependent manner. The primary objective of this study was to develop a population pharmacokinetic model of dorzagliatin to evaluate the influence of covariates, such as demographic...
Voriconazole is an important broad-spectrum anti-fungal drug with nonlinear pharmacokinetics. The aim of this single centre fixed-sequence open-label drug–drug interaction trial in healthy participants (N = 17) was to determine whether microdosed probe drugs for CYP3A and CYP2C19 reliably predict voriconazole clearance (CLVRZ). At baseline, a single oral microdose of the paradigm...
Brigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor designed to overcome mechanisms of resistance associated with crizotinib, is approved for the treatment of ALK-positive advanced or metastatic non-small cell lung cancer. After oral administration of single doses of brigatinib 30–240 mg, the median time to reach maximum plasma concentration ranged from 1 to...
Darolutamide is a next-generation androgen receptor signaling inhibitor (ARSI) currently approved for the treatment of nonmetastatic castration-resistant prostate cancer (nmCRPC) and metastatic hormone sensitive prostate cancer (mHSPC). Studies suggest that darolutamide also has the potential to be used to treat other stages of prostate cancer (PC), suggesting that its...
SPI-62 is a small-molecule 11β-hydroxysteroid dehydrogenase type 1 (HSD-1) inhibitor exhibiting complicated nonlinear pharmacokinetics (PK) in human. Previously, we developed a target-mediated drug disposition (TMDD) model to characterize the substantial nonlinear PK of SPI-62. The aim of the current analysis was to perform population PK/PD analysis to further link SPI-62...
Difelikefalin, a selective kappa-opioid receptor agonist, is the first approved treatment for moderate-to-severe pruritus in patients with end-stage renal disease (ESRD) on hemodialysis (HD) in the USA and Europe. The purpose of this open-label study was to investigate the pharmacokinetics and disposition of [14C]difelikefalin following a single intravenous dose in subjects with...
Relugolix is a gonadotropin-releasing hormone receptor antagonist. Relugolix 40-mg monotherapy is associated with vasomotor symptoms and long-term bone mineral density loss due to hypoestrogenism. This study assessed whether the addition of estradiol (E2) 1 mg and norethindrone acetate (NETA) 0.5 mg to relugolix 40 mg (relugolix combination therapy) provides systemic E2...
As a result of changes in physiology during pregnancy, the pharmacokinetics (PK) of drugs can be altered. It is unclear whether under- or overexposure occurs in pregnant cancer patients and thus also whether adjustments in dosing regimens are required. Given the severity of the malignant disease and the potentially high impact on both the mother and child, there is a high unmet...
The impact of liver cirrhosis on the activity of UDP-glucuronosyltransferases (UGTs) is currently not well characterized. We investigated the glucuronidation capacity and glucuronide accumulation in patients with liver cirrhosis. We administered the Basel phenotyping cocktail (caffeine, efavirenz, flurbiprofen, omeprazole, metoprolol, midazolam) to patients with liver cirrhosis...
A genetic variant explaining a part of the exposure of many kinase inhibitors (KIs) is the single nucleotide polymorphism (SNP) CYP3A4*22, resulting in less CYP3A4 enzyme activity. The primary aim of this study was to investigate if the systemic exposure is non-inferior after a dose reduction of KIs metabolized by CYP3A4 in CYP3A4*22 carriers compared to patients without this SNP...
Historically, dosing of tacrolimus is guided by therapeutic drug monitoring (TDM) of the whole blood concentration, which is strongly influenced by haematocrit. The therapeutic and adverse effects are however expected to be driven by the unbound exposure, which could be better represented by measuring plasma concentrations. We aimed to establish plasma concentration ranges...
Extracorporeal membrane oxygenation (ECMO) is an established advanced life support system, providing temporary cardiac and/or respiratory support in critically ill patients. Fungal infections are associated with increased mortality in patients on ECMO. Antifungal drug dosing for critically ill patients is highly challenging because of altered pharmacokinetics (PK). PK changes...
An important barrier to HIV prevention among transgender women (TGW) is the concern that oral pre-exposure prophylaxis (PrEP) negatively affects the efficacy of feminizing hormone therapy (FHT). We aimed to assess the impact of PrEP on FHT pharmacokinetics (PK) among TGW from Brazil. We performed a drug-drug interaction sub-study among TGW enrolled in a daily oral PrEP...
Alteplase is a recombinant tissue plasminogen activator used for thrombolytic treatment in several indications and is currently approved in Europe under the brand name Actilyse®. The current manufacturing process for alteplase was recently modified to meet increasing global demands. The aim of this randomized, open-label, adaptive two-stage design, two-way crossover study was to...
Pentobarbital pharmacokinetics (PK) remain elusive and the therapeutic windows narrow. Administration is frequent in critically ill children with refractory status epilepticus (SE) and severe traumatic brain injury (sTBI). To investigate pentobarbital PK in SE and sTBI patients admitted to the paediatric intensive care unit (PICU) with population-based PK (PopPK) modelling and...
Posaconazole (PSZ) is a triazole antifungal for the management of invasive fungal disease (IFD) in adults and children. Although PSZ is available as an intravenous (IV) solution, oral suspension (OS) and delayed-release tablets (DRTs), OS is the preferred formulation for pediatric use because of potential safety concerns associated with an excipient in the IV formulation and...
Up to 90% of patients with castration-resistant prostate cancer (CRPC) will develop symptomatic bone metastases requiring pain medication, with opioids being the mainstay of therapy in treating moderate and severe pain. Enzalutamide is an androgen receptor antagonist for the treatment of CRPC and a strong inducer of cytochrome P450 (CYP)3A4. Hereby, enzalutamide potentially...
Midazolam is the preferred clinical probe drug for assessing CYP3A activity. We have previously shown substantial intraindividual variability in midazolam absolute bioavailability and clearance in patients with obesity before and after weight loss induced by gastric bypass or a strict diet. The objective was to describe intraindividual variability in absolute bioavailability and...
Information on the distribution of chemotherapeutic drugs to breast milk is scarce, and reports are limited to small sample sizes. Anecdotal pharmacokinetic data have typically been acquired from lactating but non-breastfeeding patients who collect breast milk by means of an expression pump, which might not necessarily be representative for a breastfeeding population due to...
The type I interferon (IFN) signaling pathway is implicated in the pathogenesis of systemic lupus erythematosus (SLE). Anifrolumab is a monoclonal antibody that targets the type I IFN receptor subunit 1. Anifrolumab is approved in several countries for patients with moderate to severe SLE receiving standard therapy. The approved dosing regimen of anifrolumab is a 300-mg dose...
Spinal muscular atrophy (SMA) is a progressive neuromuscular disease caused by insufficient levels of survival motor neuron (SMN) protein. Risdiplam (EvrysdiTM) increases SMN protein and is approved for the treatment of SMA. Risdiplam has high oral bioavailability and is primarily eliminated through hepatic metabolism by flavin-containing monooxygenase3 (FMO3) and cytochrome P450...