Artemether-lumefantrine dosing for malaria treatment in young children and pregnant women: A pharmacokinetic-pharmacodynamic meta-analysis.

BACKGROUND: The fixed dose combination of artemether-lumefantrine (AL) is the most widely used treatment for uncomplicated Plasmodium falciparum malaria. Relatively lower cure rates and lumefantrine levels have been reported in young children and in pregnant women during their second and third trimester. The aim of this study was to investigate the pharmacokinetic and pharmacodynamic properties of lumefantrine and the pharmacokinetic properties of its metabolite, desbutyl-lumefantrine, in order to inform optimal dosing regimens in all patient populations. METHODS AND FINDINGS: A search in PubMed, Embase, ClinicalTrials.gov, Google Scholar, conference proceedings, and the WorldWide Antimalarial Resistance Network (WWARN) pharmacology database identified 31 relevant clinical studies published between 1 January 1990 and 31 December 2012, with 4,546 patients in whom lumefantrine concentrations were measured. Under the auspices of WWARN, relevant individual concentration-time data, clinical covariates, and outcome data from 4,122 patients were made available and pooled for the meta-analysis. The developed lumefantrine population pharmacokinetic model was used for dose optimisation through in silico simulations. Venous plasma lumefantrine concentrations 7 days after starting standard AL treatment were 24.2% and 13.4% lower in children weighing <15 kg and 15-25 kg, respectively, and 20.2% lower in pregnant women compared with non-pregnant adults. Lumefantrine exposure decreased with increasing pre-treatment parasitaemia, and the dose limitation on absorption of lumefantrine was substantial. Simulations using the lumefantrine pharmacokinetic model suggest that, in young children and pregnant women beyond the first trimester, lengthening the dose regimen (twice daily for 5 days) and, to a lesser extent, intensifying the frequency of dosing (3 times daily for 3 days) would be more efficacious than using higher individual doses in the current standard treatment regimen (twice daily for 3 days). The model was developed using venous plasma data from patients receiving intact tablets with fat, and evaluations of alternative dosing regimens were consequently only representative for venous plasma after administration of intact tablets with fat. The absence of artemether-dihydroartemisinin data limited the prediction of parasite killing rates and recrudescent infections. Thus, the suggested optimised dosing schedule was based on the pharmacokinetic endpoint of lumefantrine plasma exposure at day 7. CONCLUSIONS: Our findings suggest that revised AL dosing regimens for young children and pregnant women would improve drug exposure but would require longer or more complex schedules. These dosing regimens should be evaluated in prospective clinical studies to determine whether they would improve cure rates, demonstrate adequate safety, and thereby prolong the useful therapeutic life of this valuable antimalarial treatment.

Patient satisfaction with ExtaviPro™ 30G, a new auto-injector for administering interferon ß-1b in multiple sclerosis: results from a real-world, observational EXCHANGE study.

BACKGROUND: Patients with multiple sclerosis (MS) receiving long-term, subcutaneous interferon ß-1b (IFN ß-1b; Extavia®) often experience injection-site reactions and injection-site pain, which together with other side-effects (such as flu-like symptoms) result in suboptimal treatment compliance/adherence. The EXCHANGE study evaluated patient satisfaction with IFN ß-1b treatment, administered using ExtaviPro™ 30G, a new auto-injector, in a real-world setting. METHODS: This 26-week, open-label, prospective, non-interventional, observational, multi-country multi-centre study enrolled patients with MS who had been treated with IFN ß-1b or other disease-modifying therapies with a self-administered auto-injector for ≥3 months and who were planned to switch to IFN ß-1b treatment administered using ExtaviPro™ 30G as part of routine clinical care. Patient-reported outcomes included overall patient satisfaction (primary outcome) and satisfaction associated with treatment effectiveness, convenience and side-effects, assessed using Treatment Satisfaction Questionnaire for Medication (TSQM)-14. The changes in TSQM scores from baseline to Week 26 were reported. All data were analysed using SAS statistical software (version 9.4). RESULTS: Of the 336 patients enrolled, 324 were included in the analysis. At baseline, mean ± standard deviation (SD) age of patients was 41.8 ± 11.3 years and 68.2% were women. The mean ± SD of MS disease duration was 6.9 ± 6.6 years, and the majority of patients (94.1%) had relapsing-remitting MS. The mean ± SD of TSQM score for overall patient satisfaction at Week 26 was 75.6 ± 16.46 (baseline, 73.0 ± 17.14; p = 0.0342). The mean ± SD of TSQM subscale scores for patient satisfaction with effectiveness, side-effects and convenience were 75.0 ± 18.65 (baseline, 71.6 ± 19.45; p = 0.0356), 88.5 ± 18.98 (baseline, 82.7 ± 22.93; p = 0.0002) and 77.6 ± 16.72 (baseline, 71.1 ± 17.53; p < 0.0001), respectively. CONCLUSION: The results from this real-world study suggest that administering IFN ß-1b with the new ExtaviPro™ auto-injector significantly improves overall patient satisfaction, including satisfaction associated with effectiveness, side-effects and convenience in MS patients.

Cardiac and vascular effects of fingolimod: mechanistic basis and clinical implications.

Fingolimod, a sphingosine-1-phosphate receptor (S1PR) modulator, was the first oral disease-modifying therapy approved for relapsing forms of multiple sclerosis; it reduces autoreactive lymphocytes' egress from lymphoid tissues by down-regulating S1PRs. Sphingosine-1-phosphate signaling is implicated in a range of physiologic functions, and S1PRs are expressed differentially in various tissues, including the cardiovascular system. Modulation of S1PRs on cardiac cells provides an explanation for the transient effects of fingolimod on heart rate and atrioventricular conduction at initiation of fingolimod therapy, and for the mild but more persistent effects on blood pressure observed in some patients on long-term treatment. This review describes the nontherapeutic actions of fingolimod in the context of sphingosine-1-phosphate signaling in the cardiovascular system, as well as providing a summary of the associated clinical implications useful to physicians considering initiation of fingolimod therapy in patients. A transient reduction in heart rate (mean decrease of 8 beats per minute) and, less commonly, a temporary delay in atrioventricular conduction observed in some patients when initiating fingolimod therapy are both due to activation of S1PR subtype 1 on cardiac myocytes. These effects are a reflection of fingolimod first acting as a full S1PR agonist and thereafter functioning as an S1PR antagonist after down-regulation of S1PR subtype 1 at the cell surface. For most individuals, first-dose effects of fingolimod are asymptomatic, but all patients need to be monitored for at least 6 hours after the first dose, in accordance with the label recommendations.

Terbinafine hydrochloride oral granules versus oral griseofulvin suspension in children with tinea capitis: results of two randomized, investigator-blinded, multicenter, international, controlled trials.

BACKGROUND: Although griseofulvin is currently considered the primary antifungal agent used to treat tinea capitis in many countries, increasingly higher doses and longer durations of treatment are becoming necessary to achieve effective treatment. Alternative antifungal therapies with shorter/simpler treatment regimens may be important to develop for this indication. OBJECTIVE: To compare the efficacy and safety of a new pediatric formulation of terbinafine hydrochloride oral granules with griseofulvin oral suspension in the treatment of tinea capitis. METHOD: Children (4-12 years of age) with clinically diagnosed and potassium hydroxide microscopy-confirmed tinea capitis were randomized in two identical studies (trial 1, trial 2) to once-daily treatment with terbinafine (5-8 mg/kg; n = 1040) or griseofulvin administered per label (10-20 mg/kg; n = 509) for a period of 6 weeks followed by 4 weeks of follow-up. End-of-study complete cure (negative fungal culture and microscopy with Total Signs and Symptoms Score [TSSS] = 0), and mycologic (negative culture and microscopy) and clinical cure (TSSS = 0) were primary and secondary efficacy variables, respectively. Efficacy analysis was based on pooled data using modified intent-to-treat population (those who received at least one dose of study drug and had positive baseline fungal culture, N = 1286). Safety assessments included monitoring of the frequency and severity of adverse events (AEs). RESULTS: Rates of complete cure and mycologic cure were significantly higher for terbinafine than for griseofulvin (45.1% vs 39.2% and 61.5% vs 55.5%, respectively; P < .05). A majority (86.7%) of patients received griseofulvin, 10 to 19.9 mg/kg per day; complete cure rate was not found to be higher among patients who received griseofulvin more than 20 mg/kg per day compared with those who received less than 20 mg/kg per day. Complete cure rate was statistically significantly greater for terbinafine compared to griseofulvin in trial 1 (46.23% vs 34.01%) but not in trial 2 (43.99% vs 43.46%). On the basis of pooled data, clinical cure was higher for terbinafine than for griseofulvin, but the difference was not found to be statistically significant (P = .10). Subgroup analyses revealed that terbinafine was significantly better than griseofulvin for all cure rates--mycologic, clinical, and complete--among patients with Trichophyton tonsurans but not Microsporum canis (P < .001). For M. canis, mycologic and clinical cure rates were significantly better with griseofulvin than with terbinafine (P < .05). Approximately 50% of patients in each group reported an AE; almost all were mild or moderate in severity. Nasopharyngitis, headache, and pyrexia were most common in both groups. There were no drug-related serious AEs, no deaths, and no significant effects on weight or laboratory parameters, including liver transaminases. LIMITATIONS: In retrospect, a difference in the distribution of infecting microorganisms between the two trials was a limitation. Stringent adherence to griseofulvin doses recommended by prescribing information but smaller than those used in current clinical practice, and exclusion of adjuvant therapies such as shampoos or topical agents, which are routinely used in practice, are other limitations. CONCLUSIONS: Data from this largest pediatric trial of terbinafine to date indicate that terbinafine is efficacious and well tolerated in the treatment of tinea capitis. Terbinafine is an effective alternative to griseofulvin against T. tonsurans tinea capitis.

Benefit-Risk Profile of Sphingosine-1-Phosphate Receptor Modulators in Relapsing and Secondary Progressive Multiple Sclerosis.

Since the approval of fingolimod, several selective sphingosine-1-phosphate receptor modulators have entered clinical development for multiple sclerosis. However, side effects can occur with sphingosine-1-phosphate receptor modulators. By considering short-term data across the drug class and longer term fingolimod data, we aim to highlight the potential of sphingosine-1-phosphate receptor modulators in multiple sclerosis, while offering reassurance that their benefit-risk profiles are suitable for long-term therapy. Short-term fingolimod studies demonstrated the efficacy of this drug class, showed that cardiac events upon first-dose administration are transient and manageable, and showed that serious adverse events are rare. Early-phase studies of selective sphingosine-1-phosphate receptor modulators also show efficacy with a similar or improved safety profile, and treatment initiation effects were reduced with dose titration. Longer term fingolimod studies demonstrated sustained efficacy and raised no new safety concerns, with no increases in macular edema, infection, or malignancy rates. Switch studies identified no safety concerns and greater patient satisfaction and persistence with fingolimod when switching from injectable therapies with no washout period. Better outcomes were seen with short than with long washouts when switching from natalizumab. The specific immunomodulatory effects of sphingosine-1-phosphate receptor modulators are consistent with the low observed rates of long-term, drug-related adverse effects with fingolimod. Short-term data for selective sphingosine-1-phosphate receptor modulators support their potential effectiveness in multiple sclerosis, and improved side-effect profiles may widen patient access to this drug class. The long-term safety, tolerability, and persistence profiles of fingolimod should reassure clinicians that sphingosine-1-phosphate receptor modulators are likely to be suitable for the long-term treatment of multiple sclerosis.

Intermittent versus continuous terbinafine in the treatment of toenail onychomycosis: a randomized, double-blind comparison.

BACKGROUND: Terbinafine is an established drug for the treatment of toenail onychomycosis. Minimizing the total dose of terbinafine and giving it intermittently could improve tolerability as well as compliance, provided efficacy is not compromised. OBJECTIVE: Two identical trials were conducted to compare the efficacy, safety and tolerability of the current standard regimen of terbinafine 250 mg daily with a new formulation of terbinafine given intermittently for three cycles of 2 weeks of treatment (350 mg daily) followed by 2 weeks off treatment. METHODS: A total of 2005 patients with a clinical diagnosis of subungual onychomycosis of the large toenail confirmed by microscopy and culture for a dermatophyte were recruited into the two trials and treated for 12 weeks. RESULTS: Patients with onychomycosis of prolonged duration (mean 9 years) and a median nail involvement of 63% with or without spikes, lateral involvement and white superficial onychomycosis (WSO) were included in the trial. The studies found a significant difference (p<0.05) in favour of standard daily dosing with terbinafine. Response rates for the primary variable complete cure (mycological and clinical cure) were lower with the new formulation in both Trial I (-5.8%; 95% CI -11.8, 0.07) and Trial II (difference -5.9%; 95% CI -12, 0.1). Both treatments were equally well tolerated, with approximately 11% of patients in both groups reporting at least one treatment-related adverse event. CONCLUSIONS: Pulsed dosing with terbinafine did not provide any clear safety advantages and was significantly less effective. Consequently, continuous treatment with terbinafine tablets remains the optimal therapy for onychomycosis.

Clinical efficacy and safety of oral terbinafine in fungal mycetoma.

OBJECTIVES: An open-label study was performed to assess the efficacy and safety of terbinafine in the treatment of eumycetoma. METHODS: Single-center, open-label study, including 27 patients with signs and symptoms of eumycetoma which had developed within 5 years and was confirmed by mycological examination. The intention-to-treat population (n=23) received 500 mg of terbinafine bid for 24-48 weeks. Efficacy evaluations included clinical signs and symptoms (e.g. sinuses open or closed, degree of tumefaction, and emission of grains either present or absent); mycological examinations from Week 24 onwards; and investigators' overall assessment of efficacy (cure, improved since baseline, unchanged since baseline, or deterioration since baseline). Safety evaluations included monitoring of adverse events, laboratory assessments, vital signs and physical examinations. RESULTS: Good clinical improvement was seen in patients who completed the study (n=20). Tumefaction was absent or improved in 80% of patients; sinuses were closed in 50% of patients, and grain emissions were absent in 65% of patients. Of the 16 patients who had repeat mycological assessment, four (25%) were mycologically cured. In the investigators' overall opinion at the end of the study, five (25%) were cured and 11 (55%) were clinically improved. The majority of adverse events reported were mild to moderate, and consistent with the known tolerability profile of terbinafine. CONCLUSION: High-dose terbinafine (1,000 mg/day) is well tolerated and clinically effective in patients with eumycetoma, a difficult-to-treat subcutaneous mycoses.