Objective:
This article reviews the published data encompassing the development, pharmacology, efficacy, and safety of brincidofovir, a nucleotide analogue DNA polymerase inhibitor developed for the ...treatment of smallpox.
Data Sources:
A literature review was conducted in PubMed, MEDLINE, and Clinicaltrials.gov from inception up to December 2022, using terms Tembexa, brincidofovir, CMX001, smallpox treatment, and variola treatment.
Study Selection and Data Extraction:
Data were limited to studies published in English language, which evaluated the efficacy and safety of brincidofovir.
Data Synthesis:
Two surrogate animal models were included in the Food and Drug Administration’s (FDA) decision to approve brincidofovir: ectromelia virus in mice and rabbitpox in rabbits. Phases 2 and 3 studies established safety for approval. Brincidofovir biweekly for the treatment of disseminated adenovirus disease resulted in all-cause mortality, ranging from 13.8% to 29%. In a study for cytomegalovirus prophylaxis, patients with clinically significant cytomegalovirus infection through week 24 posttransplant was 51.2% with brincidofovir and 52.3% with placebo.
Conclusions:
Brincidofovir adds a second oral agent to treat smallpox, with a different mechanism of action than tecovirimat. In the event of a smallpox outbreak, prompt treatment will be necessary to contain its spread. Brincidofovir shows efficacy in surrogate animal models. In healthy volunteers and individuals treated, or used as prophylaxis, for cytomegalovirus or adenovirus, the primary adverse events were gastrointestinal in addition to transient hepatotoxicity. Additionally, excessive deaths were observed in hematopoietic cell transplant patients receiving it as cytomegalovirus prophylaxis, requiring a black box warning.
Objective
This article reviews data encompassing the pharmacology, efficacy, and safety of MenACWY-TT (MenQuadfi), a conjugate vaccine to prevent meningococcal disease from serogroups A, C, W, Y.
...Data Sources
A literature review was conducted in PubMed, MEDLINE, and ClinicalTrials.gov from inception up to July 2021, using the search terms MenQuadfi, meningococcal ACWY vaccine, MCV4, and menacwy. Articles from reference lists were included to identify potential relevant literature.
Study Selection and Data Extraction
Data were limited to randomized phase II and III clinical studies published in the English language, evaluating the efficacy and safety of MenACWY-TT. Animal studies and studies not utilizing MenACWY-TT were excluded.
Data Synthesis
One phase II and 4 phase III randomized clinical studies, enrolling approximately 7700 participants, aged 2 years to 97 years old found that MenACWY-TT was noninferior when compared to established MenACWY vaccines, as measured by surrogate immunogenicity end points. In studies evaluating primary dose vaccination, conducted in those aged 2 to 97 years of age, the difference in seroresponse rates, reported by the lower bound of the 95% CI, was (A) 1.1% to 14.8%, (C) 21% to 42.2%, (Y) 7.7% to 24.6%, and (W) 8.9% to 22.5%.
Relevance to Patient Care and Clinical Practice
Despite the low incidence of meningococcal disease in the United States, meningococcal disease causes significant morbidity and mortality if not prevented.
Conclusion
MenACWY-TT is noninferior to currently approved quadrivalent meningococcal vaccines and shows similar immunogenicity and safety as both an initial vaccine for prevention as well as a booster dose.
Since its approval by the U.S. Food and Drug Administration in 2002, voriconazole has become a key component in the successful treatment of many invasive fungal infections including the most common, ...aspergillosis and candidiasis. Despite voriconazole's widespread use, optimizing its treatment in an individual can be challenging due to significant interpatient variability in plasma concentrations of the drug. Variability is due to nonlinear pharmacokinetics and the influence of patient characteristics such as age, sex, weight, liver disease, and genetic polymorphisms in the cytochrome P450 2C19 gene (CYP2C19) encoding for the CYP2C19 enzyme, the primary enzyme responsible for metabolism of voriconazole. CYP2C19 polymorphisms account for the largest portion of variability in voriconazole exposure, posing significant difficulty to clinicians in targeting therapeutic concentrations. In this review, we discuss the role of CYP2C19 polymorphisms and their influence on voriconazole's pharmacokinetics, adverse effects, and clinical efficacy. Given the association between CYP2C19 genotype and voriconazole concentrations, as well as the association between voriconazole concentrations and clinical outcomes, particularly efficacy, it seems reasonable to suggest a potential role for CYP2C19 genotype to guide initial voriconazole dose selection followed by therapeutic drug monitoring to increase the probability of achieving efficacy while avoiding toxicity.
The era of the integrase strand transfer inhibitors (INSTIs) for the treatment of human immunodeficiency virus (HIV) infection began with raltegravir in 2007. Since that time, several other INSTIs ...have been introduced including elvitegravir, dolutegravir, and, most recently, bictegravir, that have shown great utility as part of antiretroviral regimens in both treatment‐naive and treatment‐experienced patients. At present, antiretroviral guidelines fully endorse the INSTI class as part of all first‐line treatment regimens. After 10 years of experience with INSTIs, newer agents are on the horizon such as cabotegravir and MK‐2048 for potential use as either HIV pre‐exposure prophylaxis or maintenance therapy. This review provides a brief overview of the INSTI class including agents currently available and those still in development, reviews available data from both completed and ongoing clinical trials, and outlines simplification strategies using INSTIs.
Currently recommended multidrug treatment regimens for Mycobacterium avium complex (MAC) lung disease yield limited cure rates. This results, in part, from incomplete understanding of the ...pharmacokinetics and pharmacodynamics of the drugs.
To study pharmacokinetics, pharmacodynamics, and drug interactions of multidrug treatment regimens in a large cohort of patients with MAC lung disease.
We retrospectively collected pharmacokinetic data of all patients treated for MAC lung disease in the Adult Care Unit at National Jewish Health, Denver, Colorado, in the January 2006 to January 2010 period; we retrospectively calculated areas under the time-concentration curve (AUC). Minimum inhibitory concentrations (MIC) of their MAC isolates were retrieved for pharmacodynamic calculations.
We included 531 pharmacokinetic analyses, performed for 481 patients (84% females; mean age, 63 yr; mean body mass index, 21.6). Peak serum concentrations (C(max)) below target range were frequent for ethambutol (48% of patients); clarithromycin (56%); and azithromycin (35%). Concurrent administration of rifampicin led to 68%, 23%, and 10% decreases in C(max) of clarithromycin, azithromycin, and moxifloxacin. C(max)/MIC or AUC/MIC ratios associated with bactericidal activity were seldom met; 57% of patients achieved target ratios for ethambutol, versus 42% for clarithromycin, 19% for amikacin, 18% for rifampicin, and 11% for moxifloxacin.
Currently recommended regimens for MAC lung disease yield important pharmacologic interactions and low concentrations of key drugs including macrolides. Pharmacodynamic indices for rifampicin, clarithromycin, amikacin, and moxifloxacin are seldom met. This may partly explain the poor outcomes of currently recommended treatment regimens. Trials of new drugs and new dosing strategies are needed.
The treatment of infections caused by nontuberculous mycobacteria (NTM) is challenging because multidrug regimens with limited efficacy and considerable toxicity are required. Current treatment of ...NTM is largely empiric. None of the NTM drugs were specifically developed for the treatment of NTM; the rationale for their use was often extrapolated from the treatment of tuberculosis. This article reviews key features of the drugs that are most commonly used for NTM infections, and provides monitoring parameters. With this information, clinicians can make the most of the limited options available. Considerable research is needed to optimize the treatment of NTM.
Tenofovir alafenamide (TAF) is indicated for adult patients with chronic hepatitis B virus (HBV) infection with compensated liver disease at an oral dose of 25 mg/day. TAF is a more stable prodrug in ...the plasma than tenofovir disoproxil fumarate (TDF), leading to decreased plasma exposure of tenofovir. Decreased exposure is thought to reduce the risk of long‐term TDF toxicities, such as nephrotoxicity and decreased bone mineral density (BMD). TAF, a nucleotide reverse transcriptase inhibitor, has the same mechanism of action as TDF. The results of phase III primary trials and extensions showed that TAF is noninferior to TDF at suppressing the HBV viral load in treatment‐naive and treatment‐experienced HBeAg‐negative and HBeAg‐positive patients at 48 weeks, 96 weeks, and 144 weeks of therapy. The most commonly reported adverse events were headache, abdominal pain, fatigue, cough, nausea, and back pain. At all evaluated time points (out to 144 wks of treatment), patients who received TAF had less risk of nephrotoxicity and less of a decline in BMD than the patients who received TDF. TAF appears to be safe in patients with a creatinine clearance (Clcr) above 15 ml/min; however, TAF is not currently recommended in patients with an estimated Clcr below this threshold. TAF is safe in patients with mild hepatic impairment but is not currently recommended in patients with moderate or severe hepatic impairment (Child‐Pugh class B or C).
Selection of an appropriate antiretroviral regimen for the patient infected with human immunodeficiency virus can be challenging, as various considerations must be taken into account including viral ...resistance mutations, patient comorbidities, drug interactions, and the potential for drug‐related adverse effects and toxicities. Treatment is further complicated when a clinical scenario arises requiring an alteration in the dosage form. Factors ranging from dysphagia to administration through an enteral feeding tube can affect decisions regarding antiretroviral dosage forms. Limited pharmacokinetic data exist regarding the alteration of antiretroviral medications from their original form. Bioavailability may vary substantially between dosage forms, which can lead to unpredictable drug concentrations. Supratherapeutic or subtherapeutic antiretroviral drug concentrations can result in increased toxicity, virologic failure, or the emergence of drug resistance. We performed a systematic literature search to review the available antiretroviral literature on the modification of solid dosage forms as well as alternative routes of administration of oral antiretroviral agents and their application to clinical practice.
Objectives
Latent tuberculosis infection and tuberculosis disease are prevalent worldwide. However, antimycobacterial rifamycins have drug interactions with many antiretroviral drugs. We evaluated ...the effect of rifapentine on the pharmacokinetic properties of raltegravir.
Methods
In this open-label, fixed-sequence, three-period study, 21 healthy volunteers were given: raltegravir alone (400 mg every 12 h for 4 days) on days 1–4 of Period 1; rifapentine (900 mg once weekly for 3 weeks) on days 1, 8 and 15 of Period 2 and raltegravir (400 mg every 12 h for 4 days) on days 12–15 of Period 2; and rifapentine (600 mg once daily for 10 scheduled doses) on days 1, 4–8 and 11–14 of Period 3 and raltegravir (400 mg every 12 h for 4 days) on days 11–14 of Period 3. Plasma raltegravir concentrations were measured. ClinicalTrials.gov database: NCT00809718.
Results
In 16 subjects who completed the study, coadministration of raltegravir with rifapentine (900 mg once weekly; Period 2) compared with raltegravir alone resulted in the geometric mean of the raltegravir AUC from 0 to 12 h (AUC0–12) being increased by 71%; the peak concentration increased by 89% and the trough concentration decreased by 12%. Coadministration of raltegravir with rifapentine in Period 3 did not change the geometric mean of the raltegravir AUC0–12 or the peak concentration, but it decreased the trough concentration by 41%. Raltegravir coadministered with rifapentine was generally well tolerated.
Conclusions
The increased raltegravir exposure observed with once-weekly rifapentine was safe and tolerable. Once-weekly rifapentine can be used with raltegravir to treat latent tuberculosis infection in patients who are infected with HIV.
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