Introduction SUVN-G3031, potent and selective H3 receptor inverse agonist is being developed for the treatment of sleep related disorders. SUVN-G3031 modulates neurotransmitters involved in the ...maintenance of wakefulness and treatment of cataplexy. EEG in rodents produced wake promoting effects. Preclinical results provide a strong support for the potential therapeutic utility of SUVN-G3031 in sleep related disorders. Methods SUVN-G3031 was studied in a single-center, multifaceted phase 1 clinical studies (US IND) to evaluate its safety, tolerability, and pharmacokinetics after single and multiple ascending doses in healthy subjects. For single ascending dose evaluation, healthy subjects were dosed with 0.1, 1, 6, 12, and 20 mg of SUVN-G3031. In multiple dose evaluation, once daily dose of 1, 3, and 6 mg were administered for 14 days in healthy adult male subjects. Effect of food, gender and age on pharmacokinetics was evaluated in healthy subjects at the dose of 6 mg. SUVN-G3031 was quantified in plasma using a validated LC-MS/MS method. Safety and tolerability was evaluated based on assessments of adverse events, physical examinations, laboratory tests, vital signs, 12-lead ECGs and continuous telemetry. Results Absorption of SUVN-G3031 was rapid and exposures were dose proportional at tested doses between 0.1 to 20 mg. SUVN-G3031 achieved the projected efficacy concentrations and attained steady state on day five in tested population on multiple administration. Food, gender and age had no effect on the pharmacokinetics of SUVN-G3031. SUVN-G3031 was well tolerated up to the highest tested dose of 20 mg/day single dose or 6 mg repeated dose in healthy subjects. Conclusion SUVN-G3031 has favorable safety and pharmacokinetic profile in healthy subjects. SUVN-G3031 is well tolerated in humans with adequate plasma exposure for efficacy and favorable pharmacokinetics suitable for once a day oral administration. Phase 2 POC study for the treatment of narcolepsy is being planned in USA. Support (If Any) None
In recent years, physiologically based PharmacoKinetic (PBPK) modeling has received growing interest as a useful tool for the assessment of drug pharmacokinetics. It has been demonstrated to be ...informative and helpful to quantify the modification in drug exposure due to specific physio‐pathological conditions, age, genetic polymorphisms, ethnicity and particularly drug–drug interactions (DDIs). In this paper, the prediction success of DDIs involving various cytochrome P450 isoenzyme (CYP) modulators namely ketoconazole (a competitive inhibitor of CYP3A), itraconazole (a competitive inhibitor of CYP3A), clarithromycin (a mechanism‐based inhibitor of CYP3A), quinidine (a competitive inhibitor of CYP2D6), paroxetine (a mechanism‐based inhibitor of CYP2D6), ciprofloxacin (a competitive inhibitor of CYP1A2), fluconazole (a competitive inhibitor of CYP2C9/2C19) and rifampicin (an inducer of CYP3A) were assessed using Simcyp® software. The aim of this report was to establish confidence in each CYP‐specific modulator file so they can be used in the future for the prediction of DDIs involving new victim compounds. Our evaluation of these PBPK models suggested that they can be successfully used to evaluate DDIs in untested scenarios. The only noticeable exception concerned a quinidine inhibitor model that requires further improvement. Additionally, other important aspects such as model validation criteria were discussed.
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• In healthy subjects, GSK2248761 was shown to be safe and well tolerated with single doses up to 1200 mg once daily and with multiple doses up to 800 mg once ...daily for 7 days. Furthermore, a phase IIa monotherapy study demonstrated that GSK2248761 30 to 800 mg once daily for 7 days was well tolerated in HIV‐1–infected subjects and that doses ≥100 mg once daily were associated with antiviral activity (∼1.8 log10 copies ml−1). However, the potential for drug interactions with co‐administration of GSK2248761 and other antiretroviral medications or supportive medications is not known.
WHAT THIS STUDY ADDS
• These studies indicate that GSK2248761 was safe and well tolerated in healthy adults treated in these studies at the doses and duration of therapy evaluated. In addition, these studies indicate that few dosage modifications would be necessary if GSK2248761 were to be administered with most antiretroviral therapies or supportive medications.
AIM To evaluate potential drug interactions with antiretroviral therapies or supportive therapies for use in conjunction with the once daily, next generation non‐nucleoside reverse transcriptase inhibitor GSK2248761 in patients with HIV‐1 infection.
METHODS A series of phase I drug interaction studies was conducted.
RESULTS GSK2248761 was shown to be a weak CYP3A4 and CYP2D6 inhibitor in a clinical study with a probe cocktail. Mean plasma concentration–time profiles for atazanavir, tenofovir disoproxil fumarate/emtricitabine (TDF/FTC), darunavir (DRV, administered with ritonavir RTV), and drospirenone/ethinylestradiol were similar following co‐administration of GSK2248761. Plasma raltegravir AUC(0,τ) and Cmax increased by 18% with no change in Cτ when raltegravir was co‐administered with GSK2248761. Lopinavir (LPV) plasma AUC(0,τ), Cmax and Cτ decreased by 23%, 14% and 40%, respectively, following administration of lopinavir/ritonavir with GSK2248761. Atorvastatin, rosuvastatin and simvastatin AUC(0,∞) and Cmax increased following co‐administration with GSK2248761, with the largest changes observed for simvastatin (3.7‐fold and 4.3‐fold). Changes in maximum and extent of GSK2248761 exposure were marginal after co‐administration with atazanavir, TDF/FTC and raltegravir compared with GSK2248761 administered alone. Co‐administration of GSK2248761 with DRV/RTV and LPV/RTV increased plasma GSK2248761 exposures by 1.25‐ to ≤2‐fold compared with GSK2248761 administered alone, and increases in GSK2248761 exposure were higher following single dose co‐administration of DRV/RTV or LPV/RTV compared with multiple doses. There were few drug‐related AEs, and no treatment‐related trends in blood chemistry, haematology, urinalysis, vital signs or ECG findings.
CONCLUSIONS These studies indicate that GSK2248761 was safe and well tolerated in healthy adults treated in these studies at the doses and duration of therapy evaluated.
Many antibiotics carry caution stickers that warn against alcohol consumption. Data regarding concurrent use are sparse. An awareness of data that address this common clinical scenario is important ...so health care professionals can make informed clinical decisions and address questions in an evidence-based manner. The purpose of this systematic review was to determine the evidence behind alcohol warnings issued for many common antimicrobials. The search was conducted from inception of each database to 2018 using PubMed, Medline via Ovid, and Embase. It included studies that involved interactions, effects on efficacy, and toxicity/adverse drug reactions (ADR) due to concomitant alcohol consumption and antimicrobials. All interactions were considered in terms of three components: (i) alteration in pharmacokinetics/pharmacodynamics (PK/PD) of antimicrobials and/or alcohol, (ii) change in antimicrobial efficacy, and (iii) development of toxicity/ADR. Available data support that oral penicillins, cefdinir, cefpodoxime, fluoroquinolones, azithromycin, tetracycline, nitrofurantoin, secnidazole, tinidazole, and fluconazole can be safely used with concomitant alcohol consumption. Data are equivocal for trimethoprim-sulfamethoxazole. Erythromycin may have reduced efficacy with alcohol consumption, and doxycycline may have reduced efficacy in chronic alcoholism. Alcohol low in tyramine may be consumed with oxazolidinones. The disulfiram-like reaction, though classically associated with metronidazole, occurs with uncertain frequency and with varied severity. Cephalosporins with a methylthiotetrazole (MTT) side chain or a methylthiodioxotriazine (MTDT) ring, ketoconazole, and griseofulvin have an increased risk of a disulfiram-like reaction. Alcohol and antimicrobial interactions are often lacking evidence. This review questions common beliefs due to poor, often conflicting data and identifies important knowledge gaps.
The safety of switching between generic products of antiseizure medications (ASMs) continues to be a hot topic in epilepsy management. The main reason for concern relates to the uncertainty on ...whether, and when, two generics found to be bioequivalent to the same brand (reference) product are bioequivalent to each other, and the risk of a switch between generics resulting in clinically significant changes in plasma ASM concentrations. This article addresses these concerns by discussing the distinction between bioequivalence and statistical testing for significant difference, the importance of intra‐subject variability in interpreting bioequivalence studies, the stricter regulatory bioequivalence requirements applicable to narrow‐therapeutic‐index (NTI) drugs, and the extent by which currently available generic products of ASMs comply with such criteria. Data for 117 oral generic products of second‐generation ASMs approved in Europe by the centralized, mutual recognition or decentralized procedure were analyzed based on a review of publicly accessible regulatory assessment reports. The analysis showed that for 99% of generic products assessed (after exclusion of gabapentin products), the 90% confidence intervals (90% CIs) of geometric mean ratios (test/reference) for AUC (area under the drug concentration vs time curve) were narrow and wholly contained within the acceptance interval (90%–111%) applied to NTI drugs. Intra‐subject variability for AUC was <10% for 53 (88%) of the 60 products for which this measure was reported. Many gabapentin generics showed broader, 90% CIs for bioequivalence estimates, and greater intra‐subject variability, compared with generics of other ASMs. When interpreted within the context of other available data, these results suggest that any risk of non‐bioequivalence between these individual generic products is small, and that switches across these products are not likely to result in clinically relevant changes in plasma drug exposure. The potential for variability in exposure when switching across generics is likely to be greatest for gabapentin.
•PNIPAAm-g-chitosan/PCL-Diol-b-PU core-shell nanofibers were synthesized.•Paclitaxel and 5-FU anticancer drugs were incorporated into the nanofibers.•The nanofibers surface was coated by magnetic ...gold nanoparticles.•The nanofibers was examined toward 4T1 breast cancer cells in vitro and in vivo.•The inhibition of tumor growth by the nanofibers during 10 days was obtained.
The poly (ε-caprolactonediol) based polyurethane (PCL-Diol-b-PU)/poly(N-isopropylacrylamide)-grafted-chitosan (PNIPAAm-g-chitosan) core-shell nanofibers were synthesized via coaxial electrospinning process. Paclitaxel and 5-FU anticancer drugs were incorporated into the core of nanofibers. The nanofibers surface was coated using magnetic gold nanoparticles and the potential of synthesized nanofibers was investigated for the sustained release of paclitaxel and 5-FU toward 4T1 breast cancer cells death in vitro and in vivo. The synthesized magnetic nanoparticles were characterized using SEM, TEM, XRD and DLS analysis. The surface morphology of nanofibers was studied under various applied voltage and different shell flow rates. The paclitaxel and 5-FU release profiles from nanofibers were examined under acidic and physiological pH. The maximum 4T1 cell killing was found to be 78% using magnetic gold coated-nanofibers in the presence of external magnetic field. The SEM images after incubation of nanofibers in 4T1 breast cancer cells indicated the well adhesion of cells on the nanofibers surface. The in vivo studies showed that the tumor volume did not change during 10 days. The minimum increase in tumor volume was obtained using paclitaxel and 5-FU loaded-nanofibers coated by the magnetic gold nanoparticles. The obtained results demonstrated the high therapeutic efficiency of synthesized nanofibrous carrier toward breast cancer treatment.
Application of information on regional intestinal permeability has been identified as a key aspect of successful pharmaceutical product development. This study presents the results and evaluation of ...an approach for the indirect estimation of site-specific in vivo intestinal effective permeability (P eff) in humans. Plasma concentration–time profiles from 15 clinical studies that administered drug solutions to specific intestinal regions were collected and analyzed. The intestinal absorption rate for each drug was acquired by deconvolution, using historical intravenous data as reference, and used with the intestinal surface area and the dose remaining in the lumen to estimate the P eff. Forty-three new P eff values were estimated (15 from the proximal small intestine, 11 from the distal small intestine, and 17 from the large intestine) for 14 active pharmaceutical ingredients representing a wide range of biopharmaceutical properties. A good correlation (r 2 = 0.96, slope = 1.24, intercept = 0.030) was established between these indirect jejunal P eff estimates and jejunal P eff measurements determined directly using the single-pass perfusion double balloon technique. On average, P eff estimates from the distal small intestine and large intestine were 90% and 40%, respectively, of those from the proximal small intestine. These results support the use of the evaluated deconvolution method for indirectly estimating regional intestinal P eff in humans. This study presents the first comprehensive data set of estimated human regional intestinal permeability values for a range of drugs. These biopharmaceutical data can be used to improve the accuracy of gastrointestinal absorption predictions used in drug development decision-making.
Serum IgG concentration-time data were analyzed using non-compartmental methods to generate PK parameters. Results Seventeen patients (9 females, mean age of 30.6 years, all Caucasian) were included ...in the PK analysis; 15 of them provided PK samples for both weekly and biweekly regimens.
The two direct-acting antiviral (2D) regimen of ombitasvir and paritaprevir (administered with low-dose ritonavir) is being developed for treatment of genotype subtype 1b and genotypes 2 and 4 ...chronic hepatitis C virus (HCV) infection. Drug-drug interactions were evaluated in healthy volunteers to develop dosing recommendations for HCV-infected subjects. Mechanism-based interactions were evaluated for ketoconazole, pravastatin, rosuvastatin, digoxin, warfarin, and omeprazole. Interactions were also evaluated for duloxetine, escitalopram, methadone, and buprenorphine-naloxone. Ratios of geometric means with 90% confidence intervals for the maximum plasma concentration and the area under the plasma concentration-time curve were estimated to assess the magnitude of the interactions. For most medications, coadministration with the 2D regimen resulted in a <50% change in exposures. Ketoconazole, digoxin, pravastatin, and rosuvastatin exposures increased by up to 105%, 58%, 76%, and 161%, respectively, and omeprazole exposures decreased by approximately 50%. Clinically meaningful changes in ombitasvir, paritaprevir, or ritonavir exposures were not observed. In summary, all 11 medications evaluated can be coadministered with the 2D regimen, with most medications requiring no dose adjustment. Ketoconazole, digoxin, pravastatin, and rosuvastatin require lower doses, and omeprazole may require a higher dose. No dose adjustment is required for the 2D regimen.
Background Deucravacitinib is a first-in-class, oral, selective, allosteric tyrosine kinase 2 (TYK2) inhibitor approved in multiple countries for the treatment of adults with plaque psoriasis.¹ ² ...Deucravacitinib binds the unique TYK2 regulatory domain, conferring greater functional selectivity vs JAK inhibitors, which bind the catalytic domain. Deucravacitinib showed superior efficacy vs placebo in a phase 2 trial in SLE (NCT03252587).³ This analysis assessed the pharmacokinetics (PK), selectivity profile compared to JAK inhibitors, and exposure-response (E-R) relationship for efficacy and safety of deucravacitinib in SLE. Methods In the phase 2 trial, patients with active SLE were randomized 1:1:1:1 to placebo or deucravacitinib (3 mg BID, 6 mg BID, 12 mg QD). PK analysis included pooled concentration data from 266 SLE patients and 328 phase 1 participants. IC50 was determined by in vitro whole blood assays and plotted against PK profiles. E-R analyses included data from 356 patients. Logistic regression analyses assessed the relationship between deucravacitinib exposure and probability of achieving efficacy endpoints and safety events at weeks 32 and 48. Results Deucravacitinib PK in SLE patients was not meaningfully different from that in phase 1 participants. At 12 mg QD, deucravacitinib Cmax was 8-fold lower than JAK 1/3 IC50 and 47-fold lower than JAK 2/2 IC50 (figure 1). In the E-R analyses, the probability of achieving SRI(4) and BICLA at week 32 increased with increasing deucravacitinib CminSS, with 3 mg BID providing near-maximal response. The E-R relationship for infection and infestation was relatively flat, while skin and subcutaneous tissue disorders increased with increasing deucravacitinib CminSS. These E-R relationships were similar at week 48. Conclusions Deucravacitinib PK in SLE patients is not meaningfully different from that in phase 1 participants. At clinically relevant exposures, deucravacitinib demonstrates highly selective inhibition of TYK2 vs JAK 1/2/3. The deucravacitinib E-R relationships are well characterized for various efficacy endpoints and safety events. Abstract LP-182 Figure 1 Plasma concentration-time profile of deucravacitinib, baricitinib, tofacitinib, and upadacitinib along with their respective whole blood IC50 curves Figure omitted. See PDF References Armstrong A, et al. J Am Acad Dermatol 2023;88(1):29–39. Strober B, et al. J Am Acad Dermatol 2023;88(1):40–51. Morand E, et al. Arthritis Rheumatol 2022 Nov 11 (Epub ahead of print).
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