Cutting-edge pharmacotherapy for hepatitis C virus infection: a comprehensive review.

INTRODUCTION: Pharmacotherapy against hepatitis C virus (HCV) infection has tremendously improved since the advent of interferon (IFN)-free direct-acting antivirals (DAAs). Additionally, fixed-dose pangenotypic DAAs, which are safe, potent, easy for use, and can cover a wide spectrum of patients, have been recommended by professional guidelines for DAA-naïve and DAA-experienced patients with HCV. AREAS COVERED: We review the pharmacokinetics, pharmacodynamics, and potential drug-drug interactions (DDIs) of fixed-dose pangenotypic DAA regimens, including glecaprevir/pibrentasvir (GLE/PIB), sofosbuvir/velpatasvir (SOF/VEL), and sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX). Additionally, we summarize the efficacy and safety of these regimens in clinical trials as well as real-world studies for treating different populations. Lastly, we discuss unmet medical needs in managing HCV in the era of fixed-dose pangenotypic DAAs. EXPERT OPINION: Protease inhibitors (PIs), including GLE and VOX, are prone to have more frequent DDIs, compared to the non-structural (NS) 5A and 5B inhibitors. These regimens are generally well tolerated and can be applied to different populations, except for the contraindicated use of PI-containing DAA regimens in decompensated cirrhosis. Using the first-line GLE/PIB and SOF/VEL can eradicate HCV in more than 95% of DAA-naïve patients across different populations. The viral cure usually exceeds 95% when using the rescue SOF/VEL/VOX regimen for prior DAA failures.

Pharmacokinetics of Sofosbuvir/Velpatasvir and efficacy of an alternate-day treatment in hemodialysis patients with chronic hepatitis C infection.

Sofosbuvir/Velpatasvir (SOF/VEL) is a combination drug used for chronic hepatitis C (HCV) infection. However, limited information exists regarding the pharmacokinetics of SOF/VEL and its metabolites in hemodialysis patients. We conducted a prospective investigation of the pharmacokinetic parameters of SOF/VEL after a single dose of SOF/VEL (400/100 mg) on days with and without dialysis in 12 Thai hemodialysis patients with chronic HCV infection, who had been undergoing hemodialysis for a duration of 0.5-20 years. Blood samples were collected before dose (0) and 0.5, 1.0, 2.0, 2.5, 3.0, 3.5, 4.0, 5.0, 6.0, 8.0, and 12.0 h after dose. Dialysate samples were also collected before dose (0) and 1.0, 2.0, 3.0, and 4.0 h after dose. Plasma and dialysate samples were quantified for SOF and its metabolite, GS-331007, and VEL concentrations using a fully validated LCMS technique. In addition, a preliminary efficacy study was conducted using the proposed SOF/VEL dose reduction regimen in all patients. No differences in SOF/VEL PK parameters between on- and off-dialysis studies. On the contrary, GS-331007 exhibited a 30% reduction in the area under the plasma concentration-time curve from time 0 to 24 h (AUC0-24h) on dialysis days compared with non-dialysis days (AUC0-24h ratio 0.68 vs. 1.04, respectively). The dialysis clearance of SOF and GS-331007 was 9.35 (8.72-15.11) and 8.89 (8.52-14.07) mL/min, respectively. Subsequently, an alternate-day regimen of SOF/VEL (400/100 mg) was administered for 12 weeks, resulting in an undetectable plasma HCV viral load without side effects. Further clinical studies are warranted to validate the efficacy and safety of our proposed dose reduction regimen.

Protocol of a drug-drug interaction study between bictegravir/emtricitabine/tenofovir alafenamide and feminizing hormones in trans women living with HIV.

AIMS: Trans/transfeminine women are disproportionally affected by HIV. Concerns regarding negative drug-drug interactions (DDIs) between ART drugs and gender-affirming hormone therapy (GAHT), specifically feminizing hormone therapy (FHT), may contribute to the lower ART uptake by trans women with HIV compared with their cis counterparts. The aim of this study is to investigate the bidirectional pharmacokinetic effects of components of FHT regimens (oral oestradiol and androgen-suppressing medications) with the ART regimen (bictegravir/emtricitabine/tenofovir alafenamide [B/F/TAF)]. METHODS: We present a protocol for a three-armed, parallel-group, longitudinal (6-month), DDI study. Group 1 includes 15 3trans women with HIV taking FHT and ART; group 2 includes 15 premenopausal cis women with HIV taking ART; group 3 includes 15 trans women without HIV taking FHT. Women with HIV must be on or switch to B/F/TAF at baseline and be virally suppressed for ≥3 months. Trans women must be taking a stable regimen of ≥2 mg daily oral oestradiol and an anti-androgen (pharmaceutical, and/or surgical, and/or medical) for ≥3 months. Plasma ART drug concentrations will be sampled at Month 2 and compared between groups 1 and 2. Serum oestradiol concentrations will be sampled at baseline and Month 2 visits and compared between groups 1 and 3. The primary outcomes are B/F/TAF pharmacokinetic parameters (Cmin, Cmax and AUC) and oestradiol concentrations (Cmin, C4h, Cmax and AUC) at month 2. DISCUSSION: This study is of global importance as it provides critical information regarding safe coadministration of B/F/TAF and FHT, both of which are life-saving therapies for trans women with HIV.

Bioequivalence Study of Velpatasvir/Sofosbuvir Oral Coated Tablets in Healthy Volunteers Under Fasting Conditions.

This study was conducted as a single-site, open-label, randomized, replicated crossover trial with 4 treatment periods. The aim was to evaluate the bioequivalence of a generic test drug containing velpatasvir and sofosbuvir compared to an established brand-name medication in healthy White subjects under fasting conditions. Blood samples were collected at specified intervals up to 72 hours after dosing to measure the concentrations of velpatasvir and sofosbuvir using a certified high-performance liquid chromatography with tandem mass spectrometry method. The bioequivalence of the 2 formulations was confirmed when statistical analysis showed that confidence intervals for the log-transformed peak concentration and area under the concentration-time curve from time 0 to the last quantifiable sample were within an acceptable range from 80% to 125%. Criteria for bioequivalence were met for both area under the concentration-time curve from time 0 until the last quantifiable sample and peak concentration parameters. No adverse effects were reported during this trial in both groups.

Systemic delivery of bictegravir and tenofovir alafenamide using dissolving microneedles for HIV preexposure prophylaxis.

Human immunodeficiency virus (HIV) continues to pose a serious threat to global health. Oral preexposure prophylaxis (PrEP), considered highly effective for HIV prevention, is the utilisation of antiretroviral (ARV) drugs before HIV exposure in high-risk uninfected individuals. However, ARV drugs are associated with poor patient compliance and pill fatigue due to their daily oral dosing. Therefore, an alternative strategy for drug delivery is required. In this work, two dissolving microneedle patches (MNs) containing either bictegravir (BIC) or tenofovir alafenamide (TAF) solid drug nanoparticles (SDNs) were developed for systemic delivery of a novel ARV regimen for potential HIV prevention. According to ex vivo skin deposition studies, approximately 11% and 50% of BIC and TAF was delivered using dissolving MNs, respectively. Pharmacokinetic studies in Sprague Dawley rats demonstrated that BIC MNs achieved a long-acting release profile, maintaining the relative plasma concentration above the 95% inhibitory concentration (IC95) for 3 weeks. For TAF MNs, a rapid release of drug and metabolism of TAF into TFV were obtained from the plasma samples. This work has shown that the proposed transdermal drug delivery platform could be potentially used as an alternative method to systemically deliver ARV drugs for HIV PrEP.

Simultaneous quantification of five antiretrovirals in human tissues using ultra-high performance liquid chromatography-tandem mass spectrometry methods for therapeutic drug monitoring at the sites of action.

Although antiretroviral therapy (ART) is highly effective for the treatment of HIV-1 infection to suppress virus in the blood, HIV persists in tissues. HIV persistence in the tissues is due to numerous factors, and one of those factors are antiretroviral (ARV) concentrations. ARV concentrations in tissues must be adequate to suppress HIV at the sites of action. While therapeutic drug monitoring in the plasma is well-known, drug monitoring in the tissues provides local assessments of adequate ARV exposure to prevent localized HIV resistance formation. Towards these efforts, we validated an ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS/MS) method in human tissues (cervical, rectal, and vaginal tissues) for the simultaneous quantification of five ARVs: bictegravir, cabotegravir, dolutegravir, doravirine, and raltegravir. For this assay, protein precipitation with acetonitrile with stable, isotopically-labeled internal standards followed by supernatant pre-concentration was performed. Analyte separation was accomplished using a multistep UPLC gradient mixture of 0.1 % formic acid in water (A) and acetonitrile (B) with a Waters Cortecs T3 (2.1x100 mm) column. The assay was extensively validated as per the United States Food and Drug Administration Bioanalytical Method Validation Guidance over a clinically observed range (0.05-50 ng/mL) with superb linearity (R2 > 0.99 across all ARVs). The assay run time was 8.5 min. This analytical method achieves appropriate performance of trueness (85.5-107.4 %), repeatability, and precision (CV < 15 %). Our method will be employed for the therapeutic monitoring of guideline-recommended ARVs in human tissues for monitoring therapeutic efficacy in HIV treatment and prevention research efforts.

JEWELFISH: 24-month results from an open-label study in non-treatment-naïve patients with SMA receiving treatment with risdiplam.

Risdiplam is a once-daily oral, survival of motor neuron 2 (SMN2) splicing modifier approved for the treatment of spinal muscular atrophy (SMA). JEWELFISH (NCT03032172) investigated the safety, tolerability, pharmacokinetics (PK), and PK/pharmacodynamic (PD) relationship of risdiplam in non-treatment-naïve patients with SMA. JEWELFISH enrolled adult and pediatric patients (N = 174) with confirmed diagnosis of 5q-autosomal recessive SMA who had previously received treatment with nusinersen (n = 76), onasemnogene abeparvovec (n = 14), olesoxime (n = 71), or were enrolled in the MOONFISH study (NCT02240355) of the splicing modifier RG7800 (n = 13). JEWELFISH was an open-label study with all participants scheduled to receive risdiplam. The most common adverse event (AE) was pyrexia (42 patients, 24%) and the most common serious AE (SAE) was pneumonia (5 patients, 3%). The rate of AEs and SAEs decreased by > 50% from the first to the second year of treatment, and there were no treatment-related AEs that led to withdrawal from treatment. An increase in SMN protein in blood was observed following risdiplam treatment and sustained over 24 months of treatment irrespective of previous treatment. Exploratory efficacy assessments of motor function showed an overall stabilization in mean total scores as assessed by the 32-item Motor Function Measure, Hammersmith Functional Motor Scale-Expanded, and Revised Upper Limb Module. The safety profile of risdiplam in JEWELFISH was consistent with previous clinical trials of risdiplam in treatment-naïve patients. Exploratory efficacy outcomes are reported but it should be noted that the main aim of JEWELFISH was to assess safety and PK/PD, and the study was not designed for efficacy analysis. TRIAL REGISTRATION: The study was registered (NCT03032172) on ClinicalTrials.gov on January 24, 2017; First patient enrolled: March 3, 2017.

Induction effect of antiretroviral bictegravir on the expression of Abcb1, Abcg2 and Abcc1 genes associated with P-gp, BCRP and MRP1 transporters present in rat peripheral blood mononuclear cells.

BACKGROUND: Antiretrovirals have the potential to cause drug interactions leading to inefficacy or toxicity via induction of efflux transporters through nuclear receptors, altering drug concentrations at their target sites. RESEARCH DESIGN AND METHODS: This study used molecular dynamic simulations and qRT-PCR to investigate bictegravir's interactions with nuclear receptors PXR and CAR, and its effects on efflux transporters (P-gp, BCRP, MRP1) in rat PBMCs. PBMC/plasma drug concentrations were measured using LC-MS/MS to assess the functional impact of transporter expression. RESULTS: Bictegravir significantly increased the expression of ABC transporters, with Car identified as a key mediator. This suggests that bictegravir's influence on nuclear receptors could affect drug transport and efficacy at the cellular level. CONCLUSIONS: Bictegravir activates nuclear receptors enhancing efflux transporter expression. Understanding these interactions is crucial for preventing drug-drug interactions and reducing toxicity in clinical use. Combining CAR antagonists with bictegravir may prevent drug resistance and toxicity. However, these findings are based on preclinical data and necessitate further clinical trials to confirm their applicability in clinical settings.

Sofosbuvir-velpatasvir in children 3-17 years old with hepatitis C virus infection.

BACKGROUND: The safety and efficacy of sofosbuvir-velpatasvir in children aged 3-17 years with chronic hepatitis C virus (HCV) infection of any genotype were evaluated. METHODS: In this Phase 2, multicenter, open-label study, patients received once daily for 12 weeks either sofosbuvir-velpatasvir 400/100 mg tablet (12-17 years), 200/50 mg low dose tablet or oral granules (3-11 years and ≥17 kg), or 150/37.5 mg oral granules (3-5 years and <17 kg). The efficacy endpoint was sustained virologic response 12 weeks after therapy (SVR12). Dose appropriateness was confirmed by intensive pharmacokinetics in each age group. FINDINGS: Among 216 patients treated, 76% had HCV genotype 1% and 12% had genotype 3. Rates of SVR12 were 83% (34/41) among 3-5-year-olds, 93% (68/73) among 6-11-year-olds, and 95% (97/102) among 12-17-year-olds. Only two patients experienced virologic failure. The most common adverse events were headache, fatigue, and nausea in 12-17-year-olds; vomiting, cough, and headache in 6-11-year-olds; and vomiting in 3-5-year-olds. Three patients discontinued treatment because of adverse events. Four patients had serious adverse events; all except auditory hallucination (n = 1) were considered unrelated to study drug. Exposures of sofosbuvir, its metabolite GS-331007, and velpatasvir were comparable to those in adults in prior Phase 2/3 studies. Population pharmacokinetic simulations supported weight-based dosing for children in this age range. INTERPRETATION: The pangenotypic regimen of sofosbuvir-velpatasvir is highly effective and safe in treating children 3-17 years with chronic HCV infection.

Pharmacokinetics and Safety of Lurbinectedin Administrated with Itraconazole in Cancer Patients: A Drug-Drug Interaction Study.

This open-label, two-part, phase Ib drug-drug interaction study investigated whether the pharmacokinetic (PK) and safety profiles of lurbinectedin (LRB), a marine-derived drug, are affected by co-administration of itraconazole (ITZ), a strong CYP3A4 inhibitor, in adult patients with advanced solid tumors. In Part A, three patients were sequentially assigned to Sequence 1 (LRB 0.8 mg/m2, 1-h intravenous [IV] + ITZ 200 mg/day oral in Cycle 1 [C1] and LRB alone 3.2 mg/m2, 1 h, IV in Cycle 2 [C2]). In Part B, 11 patients were randomized (1:1) to receive either Sequence 1 (LRB at 0.9 mg/m2 + ITZ in C1 and LRB alone in C2) or Sequence 2 (LRB alone in C1 and LRB + ITZ in C2). Eleven patients were evaluable for PK analysis: three in Part A and eight in Part B (four per sequence). The systemic total exposure of LRB increased with ITZ co-administration: 15% for Cmax, area under the curve (AUC) 2.4-fold for AUC0-t and 2.7-fold for AUC0-∞. Co-administration with ITZ produced statistically significant modifications in the unbound plasma LRB PK parameters. The LRB safety profile was consistent with the toxicities described in previous studies. Co-administration with multiple doses of ITZ significantly altered LRB systemic exposure. Hence, to avoid LRB overexposure when co-administered with strong CYP3A4 inhibitors, an LRB dose reduction proportional to CL reduction should be applied.

Pharmacokinetics and safety of coformulated bictegravir, emtricitabine, and tenofovir alafenamide in children aged 2 years and older with virologically suppressed HIV: a phase 2/3, open-label, single-arm study.

BACKGROUND: Coformulated bictegravir, emtricitabine, and tenofovir alafenamide is a single-tablet regimen and was efficacious and well tolerated in children and adolescents with HIV (aged 6 years to <18 years) in a 48-week phase 2/3 trial. In this study, we report data from children aged at least 2 years and weighing 14 kg to less than 25 kg. METHODS: We conducted this open-label, multicentre, multicohort, single-arm study in South Africa, Thailand, Uganda, and the USA. Participants were virologically suppressed children with HIV, aged at least 2 years, weighing 14 kg to less than 25 kg. Participants received bictegravir (30 mg), emtricitabine (120 mg), and tenofovir alafenamide (15 mg) once daily, switching to bictegravir (50 mg), emtricitabine (200 mg), and tenofovir alafenamide (25 mg) upon attaining a bodyweight of at least 25 kg. The study included pharmacokinetic evaluation at week 2 to confirm the dose of coformulated bictegravir, emtricitabine, and tenofovir alafenamide for this weight band by comparing with previous adult data. Primary outcomes were bictegravir area under the curve over the dosing interval (AUCtau) and concentration at the end of the dosing interval (Ctau) at week 2, and incidence of treatment-emergent adverse events and laboratory abnormalities until the end of week 24 in all participants who received at least one dose of bictegravir, emtricitabine, and tenofovir alafenamide. This study is registered with ClinicalTrials.gov, NCT02881320. FINDINGS: Overall, 22 participants were screened (from Nov 14, 2018, to Jan 11, 2020), completed treatment with bictegravir, emtricitabine, and tenofovir alafenamide (until week 48), and entered an extension phase. The geometric least squares mean (GLSM) ratio for AUCtau for bictegravir was 7·6% higher than adults (GLSM ratio 107·6%, 90% CI 96·7-119·7); Ctau was 34·6% lower than adults (65·4%, 49·1-87·2). Both parameters were within the target exposure range previously found in adults, children, or both". Grade 3-4 laboratory abnormalities occurred in four (18%) participants by the end week 24 and six (27%) by the end of week 48. Drug-related adverse events occurred in three participants (14%) by the end of week 24 and week 48; none were severe. No Grade 3-4 adverse events, serious adverse events, or adverse events leading to discontinuation occurred by the end of week 24 and week 48. INTERPRETATION: Data support the use of single-tablet coformulated bictegravir (30 mg), emtricitabine (120 mg), and tenofovir alafenamide (15 mg) for treatment of HIV in children aged at least 2 years and weighing 14 kg to less than 25 kg. FUNDING: Gilead Sciences.

A phase I trial of lurbinectedin in combination with cisplatin in patients with advanced solid tumors.

Background In vitro/in vivo data showed synergism of cisplatin and lurbinectedin in ovarian cancer cells and grafts. This phase I trial investigated the recommended phase II dose (RD) of cisplatin and lurbinectedin combination, with (Group A) or without aprepitant (Group B), in patients with advanced solid tumors. Patients and Methods All patients received 60 mg/m2 cisplatin 90-min intravenous (i.v.) infusion followed by lurbinectedin 60-min i.v. infusion at escalating doses on Day 1 every 3 weeks (q3wk). Patients in Group A additionally received orally 125 mg aprepitant one hour before cisplatin on Day 1 and 80 mg on Days 2 and 3. Toxicity was graded according to the NCI-CTCAE v.4. Results RD for Group A was cisplatin 60 mg/m2 plus lurbinectedin 1.1 mg/m2. RD for Group B was cisplatin 60 mg/m2 plus lurbinectedin 1.4 mg/m2. The most frequent grade ≥ 3 adverse events were hematological [neutropenia (41%), lymphopenia (35%), leukopenia (24%), thrombocytopenia (18%)] and fatigue (35%) in Group A (n = 17), and neutropenia (50%), leukopenia (42%), lymphopenia (29%), and fatigue (13%) and nausea (8%) in Group B (n = 24). Four patients (2 in each group) had a partial response. Disease stabilization for ≥ 4 months was observed in 4 and 10 patients, respectively. Conclusion The combination of lurbinectedin with cisplatin was not possible in meaningful therapeutic dosage due to toxicity. The addition of aprepitant in combination with cisplatin did not allow increasing the dose due to hematological toxicity, whereas omitting aprepitant increased the incidence of nausea and vomiting. Modest clinical activity was observed in general.Clinical trial registration www.ClinicalTrials.gov code: NCT01980667. Date of registration: 11 November 2013.

Sofosbuvir/velpatasvir for the treatment of hepatitis C in pediatric patients.

Introduction: Sofosbuvir/velpatasvir is a combination of direct-acting antivirals with pangenotypic activity for treatment of chronic hepatitis C virus infection. It was approved in 2020 for use in children aged 6-17 years and in June 2021 by the United States Food and Drug Administration for the age group 3-5 years.Areas covered: A literature search of PUBMED and EMBASE was conducted on April 30th and updated on June 10th. Other citations were identified in references of available literature and from ClinicalTrials.gov. The aim of the present research was to outline and discuss the pharmacokinetics, clinical efficacy, tolerability and safety of sofosbuvir/velpatasvir, exploring its actual and potential use in children and adolescents with chronic hepatitis C virus infection.Expert opinion: Five combinations of direct-acting antivirals, of whom three with pangenotypic activity, are now approved for children. No major differences in efficacy and safety profile have been described. Limited access to treatment still is a major issue, especially in low and middle-income countries.

Tetrahydrocannabinol and Its Major Metabolites Are Not (or Are Poor) Substrates or Inhibitors of Human P-Glycoprotein [ATP-Binding Cassette (ABC) B1] and Breast Cancer Resistance Protein (ABCG2).

(-)-Δ9-Tetrahydrocannabinol (THC) is the primary psychoactive constituent of cannabis. In humans, 11-hydroxy-THC (11-OH-THC) and 11-nor-9-carboxy-THC (THC-COOH) are psychoactive and nonpsychoactive circulating metabolites of THC, respectively. Whether these cannabinoids are substrates or inhibitors of human P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) is unknown. Previous animal studies suggest that THC and its metabolites could be substrates of these transporters. Therefore, we performed Transwell, cellular accumulation, and vesicular transport assays, at pharmacologically relevant concentrations of these cannabinoids, using Madin-Darby canine kidney (MDCK) II cells or plasma membrane vesicles overexpressing human P-gp or BCRP. Neither THC nor 11-OH-THC was found to be a substrate or inhibitor of P-gp or BCRP. The efflux ratio of THC-COOH in MDCKII-BCRP cells was 1.6, which was significantly decreased to 1.0 by the BCRP inhibitor Ko143. Likewise, cellular accumulation of THC-COOH was significantly increased 1.6-fold in the presence versus absence of Ko143. THC-COOH also significantly inhibited BCRP-mediated transport of Lucifer yellow, a BCRP substrate; however, THC-COOH was neither a substrate nor an inhibitor of P-gp. Collectively, these results indicate that THC and 11-OH-THC are not substrates or inhibitors (at pharmacologically relevant concentrations) of either P-gp or BCRP. THC-COOH is a weak substrate and inhibitor of BCRP, but not of P-gp. Accordingly, we predict that P-gp/BCRP will not modulate the disposition of these cannabinoids in humans. In addition, use of these cannabinoids will not result in P-gp- or BCRP-based drug interactions. SIGNIFICANCE STATEMENT: This study systematically investigated whether Δ9-tetrahydrocannabinol (THC) and its major metabolites, 11-hydroxy-THC and 11-nor-9-carboxy-THC, are substrates and/or inhibitors of human P-gp and BCRP at pharmacologically relevant concentrations. The results obtained are highly valuable for mechanistic understanding and prediction of the roles of P-gp and BCRP in determining the human pharmacokinetics, tissue distribution, and drug interactions of cannabinoids.

Afidopyropen: Challenges and impact of a toxicokinetic study designed to identify a point of inflection from dose-proportionality.

Afidopyropen is an insecticide that acts as a transient receptor potential vanilloid subtype (TRPV) channel modulator in chordotonal organs of target insects and has been assessed for a wide range of toxicity endpoints including chronic toxicity and carcinogenicity in rats and mice. The current study evaluates the toxicokinetic properties of afidopyropen and its plasma metabolites in rats at dose levels where the pharmacokinetics (PK) are linear and nonlinear in an attempt to identify a point of inflection. Based on the results of this study and depending on the analysis method used, the kinetically derived maximum dose (KMD) is estimated to be between 2.5 and 12.5 mg/kg bw/d with linearity observed at doses below 2.5 mg/kg bw/d. A defined point of inflection could not be determined. These data demonstrate that consideration of PK is critical for improving the dose-selection in toxicity studies as well as to enhance human relevance of the interpretation of animal toxicity studies. The study also demonstrates the technical difficulty in obtaining a defined point of inflection from in vivo PK data.

Umbralisib: First Approval.

Umbralisib (UKONIQ™) is an oral, first-in-class dual phosphatidylinositol 3-kinase delta (PI3Kδ) and casein kinase 1 epsilon (CK1ε) inhibitor being developed by TG Therapeutics for the treatment of various haematological malignancies. In February 2021, umbralisib received its first approval in the USA for the treatment of adults with relapsed or refractory marginal zone lymphoma (MZL) who have received ≥ 1 prior anti-CD20-based regimen, and relapsed or refractory follicular lymphoma (FL) who have received ≥ 3 prior lines of systemic therapy. Clinical studies in various haematological malignancies, including chronic lymphocytic leukaemia and non-Hodgkin's lymphoma, are underway in multiple countries. This article summarizes the milestones in the development of umbralisib leading to this first approval.

Population Pharmacokinetic-Pharmacodynamic Modeling and Covariate Analyses of Neutropenia and Thrombocytopenia in Patients With Solid Tumors Treated With Lurbinectedin.

Lurbinectedin is a selective inhibitor of oncogenic transcription. Reversible myelosuppression is its most relevant toxicity. Pharmacokinetic-pharmacodynamic analyses were conducted to characterize the time course of absolute neutrophil count and platelet count recovery and to detect and quantify the effect of relevant covariates in patients with advanced solid tumors treated with lurbinectedin. Absolute neutrophil count, platelet count, and lurbinectedin total plasma concentration were assessed in 244 patients treated with lurbinectedin with varied dosing schedules and doses. A reference extended semimechanistic pharmacokinetic-pharmacodynamic model of myelosuppression was used. Granulocyte colony-stimulating factor (G-CSF) administration was modeled as a dichotomous covariate, and platelet transfusions were included as a bolus dose into the last compartment of the model, representing the central circulation. Final models were suitable to describe the time course of absolute neutrophil count and platelet count recovery. A lurbinectedin dose of 3.2 mg/m2 every 3 weeks can be administered without primary prophylaxis with G-CSF. G-CSF followed by ≤2 dose reductions of 20%, if needed, gradually reduced grade 4 neutropenia from cycle 3 onward. BSA-based dosing reduced the incidence of grade ≥ 3 thrombocytopenia. One-week dose delays because of low absolute neutrophil count occurred in 3.5% of patients, thus supporting every-3-week administration. CYP3A inhibitors produced absolute 11.0% and 6.2% increases in grade ≥ 3 neutropenia and thrombocytopenia, respectively. Neutropenia and thrombocytopenia after lurbinectedin administration to cancer patients are noncumulative, reversible, short lasting, and clinically manageable with secondary prophylaxis of G-CSF or platelet transfusion and, if needed, dose reductions.

A phase I dose-finding, pharmacokinetics and genotyping study of olaparib and lurbinectedin in patients with advanced solid tumors.

The poly (ADP-Ribose) polymerase (PARP) inhibitor olaparib has shown antitumor activity in patients with ovarian or breast cancer with or without BRCA1/2 mutations. Lurbinectedin is an ecteinascidin that generates DNA double-strand breaks. We hypothesized that the combination of olaparib and lurbinectedin maximizes the DNA damage increasing the efficacy. A 3 + 3 dose-escalation study examined olaparib tablets with lurbinectedin every 21 days. The purpose of this phase I study is to determine the dose-limiting toxicities (DLTs) of the combination, to investigate the maximum tolerated dose (MTD), the recommended phase II dose (RP2D), efficacy, pharmacokinetics, in addition to genotyping and translational studies. In total, 20 patients with ovarian and endometrial cancers were included. The most common adverse events were asthenia, nausea, vomiting, constipation, abdominal pain, neutropenia, anemia. DLT grade 4 neutropenia was observed in two patients in dose level (DL) 5, DL4 was defined as the MTD, and the RP2D was lurbinectedin 1.5 mg/m2 + olaparib 250 mg twice a day (BID). Mutational analysis revealed a median of 2 mutations/case, 53% of patients with mutations in the homologous recombination (HR) pathway. None of the patients reached a complete or partial response; however, 60% of stable disease was achieved. In conclusion, olaparib in combination with lurbinectedin was well tolerated with a disease control rate of 60%. These results deserve further evaluation of the combination in a phase II trial.

Selecting an anti-malarial clinical candidate from two potent dihydroisoquinolones.

BACKGROUND: The ongoing global malaria eradication campaign requires development of potent, safe, and cost-effective drugs lacking cross-resistance with existing chemotherapies. One critical step in drug development is selecting a suitable clinical candidate from late leads. The process used to select the clinical candidate SJ733 from two potent dihydroisoquinolone (DHIQ) late leads, SJ733 and SJ311, based on their physicochemical, pharmacokinetic (PK), and toxicity profiles is described. METHODS: The compounds were tested to define their physicochemical properties including kinetic and thermodynamic solubility, partition coefficient, permeability, ionization constant, and binding to plasma proteins. Metabolic stability was assessed in both microsomes and hepatocytes derived from mice, rats, dogs, and humans. Cytochrome P450 inhibition was assessed using recombinant human cytochrome enzymes. The pharmacokinetic profiles of single intravenous or oral doses were investigated in mice, rats, and dogs. RESULTS: Although both compounds displayed similar physicochemical properties, SJ733 was more permeable but metabolically less stable than SJ311 in vitro. Single dose PK studies of SJ733 in mice, rats, and dogs demonstrated appreciable oral bioavailability (60-100%), whereas SJ311 had lower oral bioavailability (mice 23%, rats 40%) and higher renal clearance (10-30 fold higher than SJ733 in rats and dogs), suggesting less favorable exposure in humans. SJ311 also displayed a narrower range of dose-proportional exposure, with plasma exposure flattening at doses above 200 mg/kg. CONCLUSION: SJ733 was chosen as the candidate based on a more favorable dose proportionality of exposure and stronger expectation of the ability to justify a strong therapeutic index to regulators.

Effect of lurbinectedin on the QTc interval in patients with advanced solid tumors: an exposure-response analysis.

PURPOSE: This study assessed the effect of lurbinectedin, a highly selective inhibitor of oncogenic transcription, on the change from baseline in Fridericia's corrected QT interval (∆QTcF) and electrocardiography (ECG) morphological patterns, and lurbinectedin concentration-∆QTcF (C-∆QTcF) relationship, in patients with advanced solid tumors. METHODS: Patients with QTcF ≤ 500 ms, QRS < 110 ms, PR < 200 ms, and normal cardiac conduction and function received lurbinectedin 3.2 mg/m2 as a 1-h intravenous infusion every 3 weeks. ECGs were collected in triplicate via 12-lead digital recorder in treatment cycle 1 and 2 and analyzed centrally. ECG collection time-matched blood samples were drawn to measure lurbinectedin plasma concentration. No effect on QTc interval was concluded if the upper bound (UB) of the least square (LS) mean two-sided 90% confidence intervals (CI) for ΔQTcF at each time point was < 20 ms. C-∆QTcF was explored using linear mixed-effects analysis. RESULTS: A total of 1707 ECGs were collected from 39 patients (females, 22; median age, 56 years). The largest UB of the 90% CI of ΔQTcF was 9.6 ms, thus lower than the more conservative 10 ms threshold established at the ICH E14 guideline for QT studies in healthy volunteers. C-∆QTcF was better fit by an effect compartment model, and the 90% CI of predicted ΔQTcF at Cmax was 7.81 ms, also below the 10 ms threshold of clinical concern. CONCLUSIONS: ECG parameters and C-ΔQTcF modelling in this prospective study indicate that lurbinectedin was not associated with a clinically relevant effect on cardiac repolarization.