Clinical Pharmacology : Advances and Applications最新文献

Duchenne muscular dystrophy (DMD) is a fatal, X-linked recessive disorder characterized by progressive muscle loss and cardiorespiratory complications. Mutations in the DMD gene that eliminate the production of dystrophin protein are the underlying causes of DMD. Viltolarsen is a drug of phosphorodiamidate morpholino oligomer (PMO) chemistry, designed to skip exon 53 of the DMD gene. It aims to produce truncated but partially functional dystrophin in DMD patients and restore muscle function. Based on a preclinical study showing the ability of antisense PMOs targeting the DMD gene to improve muscle function in a large animal model, viltolarsen was developed by Nippon Shinyaku and the National Center of Neurology and Psychiatry in Japan. Following clinical trials conducted in Japan, Canada, and the United States showing significant improvements in muscle function, viltolarsen was approved for medical use in Japan in March 2020 and the United States in August 2020, respectively. Viltolarsen is a mutation-specific drug and will work for 8% of the persons with DMD who carry mutations amenable to exon 53 skipping. This review summarizes the pharmacological profile of viltolarsen, important clinical trials, and challenges, focusing on the contribution of Japanese patients and researchers in its development.

The coronavirus disease 2019 (COVID-19) pandemic is currently the largest and most serious health crisis in the world. There is no definitive treatment for COVID-19. Vaccine administration has begun in various countries, but no vaccine is 100% effective. Some people are not protected after vaccination, and there are some groups of people who cannot be vaccinated therefore, research on COVID-19 treatment still needs to be done. Of the several drugs under study, chloroquine (CQ) and hydroxychloroquine (HCQ) are quite controversial, although they have good activity against SARS-CoV-2, both drugs have serious side effects. Indonesia with its wealth of natural ingredients has one potential compound, quinine sulfate (QS), which has the same structure and activity as CQ and HCQ and a better safety profile. The aim of this article was to review the potential of QS against the SARS-Cov-2 virus and outline its safety profile. We conclude that QS has the potential to be developed as a COVID-19 treatment with a better safety profile than that of CQ and HCQ.

Secondary thrombocytosis, often referred to as a reactive thrombocytosis, is more common than primary thrombocytosis and has many potential etiologies including anemia, infection, inflammation, medications, and post-splenectomy. When considering the critically ill patient in the ICU setting potential medication-related etiologies of thrombocytosis should be included in the differential diagnosis. We present a 15-year-old adolescent with a traumatic brain injury who developed thrombocytosis that was temporally related to the administration of enoxaparin. There was a prompt return of the platelet count to normal following the discontinuation of enoxaparin therapy which led to the probable diagnosis of enoxaparin-induced thrombocytosis.

Background: Standardized DKA treatment could result in better overall safety and efficacy outcomes. The primary objective of this study is to validate the efficacy of an adapted nurse-driven DKA protocol compared to a physician-driven DKA protocol across the continuum of three hospital settings: the University of Colorado upon which the physician-driven protocol is based, Northern Light Eastern Maine Medical Center (NLEMMC), and Northern Light Sebasticook Valley Hospital (NLSVH). The secondary objective is to assess the safety of the adapted nurse-driven DKA protocol adapted at NLEMMC and NLSVH through determining the incidence of hypoglycemia and anion gap reopening.

Patients and methods: This was a retrospective, IRB-approved, multi-center study that included: patients 18 years or older who were treated with the DKA protocol at NLEMMC or NLSVH, and admitted to the emergency department between July 2015 and October 2020 with a primary diagnosis of DKA and an elevated anion gap greater than or equal to 13 mEq/L.

Results: A total of 90 patients from NLEMMC and 64 patients from NLSVH were included and compared to 111 patients from the University of Colorado who were included in the post protocol implementation group. There was no statistically significant difference in the primary outcome, time to anion gap closure, between the original University of Colorado study (10.3 hours) and the NLEMMC (10.9 hours, p = 0.420) and NLSVH (8.8 hours, p = 0.115) results presented in this study.

Conclusion: The standardized nurse-driven DKA treatment protocol at NLEMMC and NLSVH showed no statistical difference in time to anion gap closure compared to the University of Colorado study upon which it was based. This finding is particularly relevant to hospitals such as NLEMMC and NLSVH that lack provider resources and teams of endocrinologists required for the physician-driven DKA protocol.

Purpose: Definitive antiviral treatment is not available for COVID-19 infection, with the exception of remdesivir, which still evokes many doubts. Various monotherapy or combination therapies with antivirals or other agents have been tried. The present study aims to evaluate the therapeutic potential of hydroxychloroquine and lopinavir-ritonavir in combination with ribavirin in mild-severe COVID-19.

Patients and methods: A single-center, open-label, parallel-arm, stratified randomized controlled trial evaluated the therapeutic potential of combination antiviral therapies. Enrolled patients in the severe category were randomized into three groups: (A) standard treatment, (B) hydroxychloroquine+ribavirin+standard treatment, or (C) lopinavir+ritonavir+ribavirin+standard treatment; while the non-severe category comprised two groups: (A) standard treatment or (B) hydroxychloroquine+ribavirin. Combination antivirals were given for 10 days and followed for 28 days. The primary endpoints were safety, symptomatic and laboratory recovery of organ dysfunctions, and time to SARS-CoV-2 RT-PCR negative report.

Results: In total, 111 patients were randomized: 24, 23, and 24 in severe categories A, B, and C, respectively, and 20 in each of the non-severe groups. Two patients receiving ribavirin experienced drug induced liver injury, and another developed QT prolongation after hydroxychloroquine. In the severe category, 47.6%, 55%, and 30.09% in A, B, and C groups, respectively, showed symptomatic recovery, compared to 93.3% and 86.7% in A and B groups, respectively, in the non-severe category at 72 hours (P>0.05).

Conclusion: Though the results failed to show statistical superiority of the antiviral combination therapies to that of the standard therapy in both the severe and non-severe categories in symptomatic adult patients of COVID-19 due to very small sized trial, clinically hydroxychloroquine+ribavirin therapy is showing better recovery by 7.4% than standard therapy in the former category. However, results do indicate the benefit of standard therapy in the non-severe category by 6.6%. Furthermore, the dose of ribavirin needs to be reconsidered in the Indian population.

Direct oral anticoagulants (DOACs) have gained increasing popularity in clinical practice in the past decade. While DOACs have fewer associated adverse events as compared to warfarin, DOAC-induced hypersensitivity is a rare adverse event that has been reported in the literature. We describe a case of apixaban-induced hemorrhagic pruritic rash in a 62-year-old man with protein C deficiency for which he was receiving warfarin. During hospitalization for another issue, his anticoagulant was converted to apixaban. Within 6 hours of receiving the first dose of apixaban, he developed a hemorrhagic pruritic rash around his buttocks area and extending into his groin. The following day, apixaban was replaced with rivaroxaban, while the rash continued to worsen and spread further around his back. After 3 days of DOAC therapy, the patient was reverted back to warfarin and within 24 hours the rash subsided. This case report indicates a potential rare adverse drug reaction that may become more prominent given the increasing utilization of DOACs in clinical practice. Future research is needed to further investigate this adverse event and ensure that providers and patients are aware of it. Additionally, this report documents to our knowledge, the first report of an immediate hypersensitivity reaction to DOACs.

Purpose: Treatment options for gastroparesis, such as metoclopramide and domperidone, are limited because of safety concerns, which may be exacerbated in the presence of inhibitors of drug metabolism. This study evaluated the effect of itraconazole on the pharmacokinetics, safety, and tolerability of trazpiroben (previously TAK-906), a novel, peripherally selective D₂/D₃ dopamine receptor antagonist.

Methods: This was a phase 1, two-period, crossover trial in healthy participants (NCT03161405). On day 1, period 1 (days 1-3), participants received a single oral dose of trazpiroben 25 mg. During period 2 (days 4-9), participants received oral itraconazole 200 mg once daily (days 1-5) and one oral dose of trazpiroben 25 mg post itraconazole on day 4. Trazpiroben pharmacokinetics were assessed. Safety assessments included triplicate electrocardiograms.

Results: Twelve healthy males (24-45 years old) were studied. Co-administration of itraconazole increased trazpiroben area under the concentration-time curve from time 0 to infinity by 1.28-fold (90% confidence interval: 1.10, 1.49) and maximum plasma concentration (C_max) by 1.98-fold (1.64, 2.39) versus trazpiroben alone. Placebo-corrected, change from baseline in corrected QT interval at the observed geometric mean C_max for trazpiroben alone (9.53 ng/mL) and with itraconazole (18.00 ng/mL) was estimated at 1.31 ms (-0.39, 3.01) and 1.54 ms (-0.15, 3.24), respectively. There were no clinically relevant abnormalities in any safety parameters.

Conclusion: These results indicate that TAK‑906 is relatively insensitive to inhibition of cytochrome P450 3A4, and cardiovascular safety concerns associated with domperidone are unlikely to be elicited by trazpiroben under similar conditions.

Palmoplantar pustulosis (PPP) is a chronic inflammatory disorder characterized by sterile pustules predominantly involving the palms and soles. PPP is refractory to various therapies such as topical ointment, oral medicine, and phototherapies. Pustulotic arthro-osteitis (PAO) is a major comorbidity of PPP that severely impairs patients' quality of life. Recently, guselkumab, a monoclonal antibody against IL-23, has been available for the treatment of PPP in Japan. The purpose of the present review is to describe the characteristics of Japanese PPP patients and biologic therapy of PPP/PAO using guselkumab. Most Japanese dermatologists consider PPP as a distinct entity and co-existence of PPP and psoriasis is rare. However, outside Japan, PPP is often considered to be palmoplantar psoriasis, and extra-palmoplantar lesions associated with PPP are regarded as psoriasis. PPP develops or exacerbates either with or without arthralgia, following focal infections, such as tonsillitis, odontogenic infection, and sinusitis. Treatment of focal infection results in dramatic effects on cutaneous lesions as well as joint pain. By contrast, we sometimes see patients whose skin/joint symptoms do not improve after treatment of focal infection, whose focus of infection cannot be identified even in a detailed examination, and/or who refuse tonsillectomy even if strongly recommended. Such cases are considered to be indications of biologics. In this review, clinical features, pathophysiology and guselkumab therapy are discussed.

Purpose: ATI-450 is an oral, small-molecule inhibitor of the p38α mitogen-activated protein kinase (MAPK)/MAPK-activated protein kinase 2 (MK2) inflammatory signaling pathway. This phase 1, single and multiple ascending dose (SAD, MAD) study evaluated ATI-450 safety, tolerability, pharmacokinetics, and pharmacodynamics.

Patients and methods: Healthy adults were randomly assigned to SAD (10, 30, 50, 100 mg; n=24) and MAD (10, 30, 50 mg twice daily [BID] for 7 days; n=24) cohorts of ATI-450 or placebo (n=14). Safety and tolerability were evaluated through clinical and laboratory assessments. Pharmacokinetic parameters were evaluated in plasma samples; pharmacodynamic assessments included quantification of cytokine levels (tumor necrosis factor α [TNF-α], interleukin [IL]-1β, IL-6, IL-8) and phosphorylation of the MK2 downstream substrate, heat shock protein 27 (p-HSP27).

Results: The most common adverse events were headache (10/48, 20.8%), dizziness (6/48, 12.5%), upper respiratory tract infection (3/48, 6.3%), and constipation (3/48, 6.3%). Pharmacokinetics were dose-proportional, with a terminal half-life of 9‒12 hours in the MAD cohorts on day 7. Dose- and concentration-dependent inhibition of ex vivo stimulated cytokines and target biomarker was observed. On day 7, patients in the 50 mg BID dose cohort recorded mean trough drug levels that were 1.4, 2.2, 2.3, and 2.4 times greater than the IC₈₀ for TNF-α, IL-1β, IL-8, and p-HSP27, respectively. Mean C_max was 3.5, 5.4, 5.6, and 6.0 times greater than the IC₈₀ for TNF-α, IL-1β, IL-8, and p-HSP27, respectively. IL-6 inhibition >50% was noted for part of the dosing interval.

Conclusion: ATI-450 was well tolerated at the doses investigated, exhibited dose- and time-independent (ie, linear) pharmacokinetics, and dose-related pharmacodynamic effects. These results support further study of ATI-450 in immunoinflammatory diseases in phase 2 trials.

Background: Allergic rhinitis (AR) and chronic urticaria, both are treated in children with doses of second generation of antihistamines that have been mostly based on extrapolation of data obtained in adults. The objectives of this work were to develop a model to explain the pharmacokinetics (PK) of rupatadine, a second generation antihistamine, administered to children 2-11 years old and to calculate the non-compartmental PK parameters for two groups of age (2-5 and 6-11 years old) based on the individual Bayesian estimates from the selected model.

Methods: Data from two PK studies with rupatadine oral solution (1 mg/mL) were pooled: Study A, an extensive blood sampling study performed in 11 children (6-11 years old) who received a single oral dose of rupatadine; and Study B, a sparse blood sampling study in 40 children (2-5 years old) receiving multiple oral doses. A simultaneous population PK model was developed using data available for all children. Using individual Bayesian estimates from the selected model, steady-state plasma concentrations for both studies were simulated and the non-parametric PK parameters were calculated for two age groups: 2-5 years (subgroup I) and 6-11 years (subgroup II).

Results: A two-compartment model with first-order absorption and elimination with clearance depending on body weight, better described the PK of rupatadine for 2-11 year old children. The plasma clearance dependence on weight was linear. The mean (SD) non-compartment PK parameters calculated using simulated plasma profiles at steady state were: C_max, 2.54 (1.26) vs 1.96 (0.52) ng/mL; AUC_0-24h, 10.74 (3.09) vs 10.38 (4.31) ng/mL/h; and t_1/2, 12.28 (3.09) vs 15.94 (4.09) h, for children 6-11 and 2-5 years old, respectively.

Conclusions: The PK of rupatadine depends on the weight of paediatric patients but not on their age. The dosage strategy adjusted by body weight in children 2-11 years old (2.5 mL if weight 10-25 kg, and 5 mL if ≥ 25 kg) provides similar exposure between the two groups of age, and to that obtained in adults with the 10 mg dose tablet formulation.