Biopharmaceutical Characteristics of Nifurtimox Tablets for Age- and Body Weight-Adjusted Dosing in Patients With Chagas Disease.
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ABSTRACT:
SUBMITTER: Stass H
PROVIDER: S-EPMC8246722 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Unfractionated heparin dosing is unpredictable and subject to numerous pharmacokinetic changes including distribution and metabolic changes associated with obesity and age. Weight-based dosing is commonly used to better predict the dose for a patient when targeting a therapeutic range. A dosing equation that adjusts weight-based doses for age and body mass index may improve therapeutic dose prediction. We conducted a 2-phase observational study with a derivation and validation period to develop an equation to adjust weight-based unfractionated heparin for age and body mass index to target a therapeutic activated partial thromboplastin time of 60 to 80 seconds. The first phase retrospectively identified patients who acheived therapeutic anticoagulation and utilized linear regression to determine a predictive equation for weight-based dosing that adjusts for age and body mass index. The second phase prospectively identified patients in an observational manner and compared the dose of unfractionated heparin on which they became therapeutic against both the weight-based dose and the predicted dose adjusted for age and body mass index. The correlation between predictive age and body mass index adjusted dose and actual therapeutic dose was 0.703 compared to the correlation between the empiric weight-based dose and actual therapeutic dose which was 0.532 ( P = .05). Age and body mass index adjusted weight-based dosing significantly improved therapeutic dose prediction for unfractionated heparin. Further study in a prospective, randomized trial is warranted for validation of this approach in a real world setting.
| S-EPMC6714904 | biostudies-other
Project description:PurposeThe Surviving Sepsis Campaign guidelines recommend 30 mL/kg of fluids within 3 hours (30by3) of sepsis-induced hypoperfusion, but a national mandate released an allowance for dosing based on ideal instead of actual body weight (IBW/ABW) for obese patients. This study aims to determine the dose-effect of 30by3 for patients with severe sepsis or septic shock (SS/SS) with respect to body mass index (BMI) categories and secondarily, examine the clinical impact of IBW vs. ABW-based dosing.MethodsRetrospective cohort study of adults (≥18 years; n = 1,032) with SS/SS presenting to an urban, tertiary-care emergency department. Models include MEDS score, antibiotic timing, lactate, renal and heart failure, among others.ResultsThe cohort was 10.2% underweight and 28.7% obese. Overall mortality was 17.1% with 20.4% shock mortality. An exponential increase in mortality was observed for each 5 mL/kg under 30by3 for underweight (p = 0.02), but not obese patients. ABW vs IBW-30by3 dosing was reached in 80.0 vs 52.4% (underweight), 56.4 vs 56.9% (normal/overweight), and 23.3 vs 46.0% (obese). Across all BMI categories, there was increased mortality for not reaching ABW-based 30by3 dosing (OR 1.78, 95% CI 1.18-2.69) with no significant impact for IBW (OR 1.28, 95% CI 0.87 -1.91). The increased mortality for failing to reach ABW-dosed 30by3 remained for underweight patients ABW (OR 5.82, 95% CI 1.32-25.57) but not obese patients. Longer ICU stays were observed for not reaching 30by3 based on ABW (β = 2.40, 95% CI 0.84-3.95) and IBW dosing (β = 1.58, 95% CI 0.07-3.08) overall. This effect remained for obese and underweight (except IBW dosing) patients.ConclusionsAn exponential, dose-effect increase in mortality was observed for underweight patients not receiving 30by3. Therefore, the mortality impact of under-dosing may be amplified using ABW for underweight patients. Fluid dosing did not impact mortality for obese patients, but we caution against deviation from guidelines without further studies.
| S-EPMC8134624 | biostudies-literature
Project description:BackgroundGrowing evidence suggests psilocybin, a naturally occurring psychedelic, is a safe and promising pharmacotherapy for treatment of mood and substance use disorders when administered as part of a structured intervention. In most trials to date, psilocybin dose has been administered on a weight-adjusted basis rather than the more convenient procedure of administering a fixed dose.AimsThe present post hoc analyses sought to determine whether the subjective effects of psilocybin are affected by body weight when psilocybin is administered on a weight-adjusted basis and when psilocybin is administered as a fixed dose.MethodsWe analyzed acute subjective drug effects (mystical, challenging, and intensity) associated with therapeutic outcomes from ten previous studies (total N = 288) in which psilocybin was administered in the range 20 to 30 mg/70 kg (inclusive). Separate multivariate regression analyses examined the relationships between demographic variables including body weight and subjective effects in participants receiving 20 mg/70 kg (n = 120), participants receiving 30 mg/70 kg (n = 182), and participants whose weight-adjusted dose was about 25 mg (to approximate the fixed dose that is currently being evaluated in registration trials for major depressive disorder) (n = 103).ResultsIn the 20 mg/70 kg and 30 mg/70 kg weight-adjusted groups, and in the fixed dose group, no significant associations were found between subjective effects and demographic variables including body weight or sex. Across a wide range of body weights (49 to 113 kg) the present results showed no evidence that body weight affected subjective effects of psilocybin.ConclusionsThese results suggest that the convenience and lower cost of administering psilocybin as a fixed dose outweigh any potential advantage of weight-adjusted dosing.
| S-EPMC8056712 | biostudies-literature
Project description:BackgroundVenous thromboembolism (VTE) frequently occurs in hospitalized patients with coronavirus disease 2019 (COVID-19). The optimal dose of anticoagulation for thromboprophylaxis in COVID-19 is unknown.AimsTo report VTE incidence and bleeding before and after implementing a hospital-wide intensified thromboprophylactic protocol in patients with COVID-19.MethodsOn March 31, 2020, we implemented an intensified thromboprophylactic protocol consisting of 50 IU anti-Xa low molecular weight heparin (LMWH)/kg once daily at the ward, twice daily at the intensive care unit (ICU). We included all patients hospitalized in a tertiary care hospital with symptomatic COVID-19 between March 7 and July 1, 2020. The primary outcome was the incidence of symptomatic or subclinical VTE and major bleeding during admission. Routine ultrasound screening for VTE was performed whenever logistically possible.ResultsWe included 412 patients, of which 116 were admitted to the ICU. Of 219 patients with standard a prophylactic dose of LMWH, 16 (7.3%) had VTE, 10 of which were symptomatic (4.6%). Of 193 patients with intensified thromboprophylaxis, there were no symptomatic VTE cases, three incidental deep venous thrombosis cases (1.6%), and one incidental pulmonary embolism (0.5%). The major bleeding rate was 1.2% in patients with intensified thromboprophylaxis and 7.7% when therapeutic anticoagulation was needed.ConclusionIn hospitalized patients with COVID-19, there were no additional symptomatic VTEs and a reduction in incidental deep vein thrombosis after implementing systematic thromboprophylaxis with weight-adjusted prophylactic (ward) to intermediate (ICU), but not therapeutic dosed anticoagulation. This intensified thromboprophylaxis was associated with a lower risk of major bleeding compared with therapeutic dosed anticoagulation.
| S-EPMC8980774 | biostudies-literature
Project description:BackgroundDabigatran etexilate (DE), a direct oral thrombin inhibitor, has been evaluated in children with venous thromboembolism (VTE) using oral solution, pellets, or capsules.ObjectivesThis study evaluated DE pharmacokinetics (PK) in children with VTE and the appropriateness of a DE pediatric age- and weight-based dosing algorithm.Patients/methodsA population PK model was fitted to data from four single-arm and one randomized, comparative pediatric VTE studies (358 children aged birth to <18 years; 2748 PK observations) and one healthy-adult study (32 males aged <40 years; 1523 PK observations) using nonlinear mixed-effects modeling. A stepwise, covariate, model-building procedure evaluated the influence of covariates (e.g., age, body weight, body surface area [BSA]-normalized renal function, and sex). The final model was used to evaluate the pediatric dosing algorithm, with simulations comparing pediatric trough exposure with reference exposure defined for the pediatric studies.ResultsThe population PK of dabigatran was adequately described by a two-compartment model with first-order elimination and absorption. Age, weight, BSA-normalized renal function, and sex were statistically significant covariates (all P < .05). Apparent clearance increased with age (independently of body weight), diminished with decreasing BSA-normalized renal function, and was lower in females than males. All disposition parameters increased with body weight escalation (allometric scaling). Simulations confirmed that for all DE formulations, the final pediatric dosing algorithms achieved reference exposure without dose adjustment.ConclusionsUsing a population PK model of DE for children with VTE, simulations showed that the final dosing algorithms were appropriate for all DE formulations; no dose titration was needed.
| S-EPMC8251571 | biostudies-literature
Project description:Nifurtimox (NF) is one of the only two drugs currently available for Chagas disease (ChD) treatment. However, data on NF safety are scarce, and many physicians defer or refuse NF treatment because of concerns about drug tolerance. In a retrospective study of adverse drug reactions (ADRs) associated with NF treatment of ChD, children received NF doses of 10 to 15 mg/kg/day for 60 to 90 days, and adults received 8 to 10 mg/kg/day for 30 days. A total of 215 children (median age, 2.6 years; range, 0 to 17 years) and 105 adults (median age, 34 years; range, 18 to 57 years) were enrolled. Overall, 127/320 (39.7%) patients developed ADRs, with an incidence of 64/105 adults and 63/215 children (odds ratio [OR] = 3.7; 95% confidence interval [CI], 2.2 to 6.3). We observed 215 ADRs, 131 in adults (median, 2 events/patient; interquartile range for the 25th to 75th percentiles [IQR25-75], 1 to 3) and 84 in children (median, 1 event/patient; IQR25-75 = 1 to 1.5) (Padjusted < 0.001). ADRs were mainly mild and moderate. Severe ADRs were infrequent (1.2% in children and 0.9% in adults). Nutritional, central nervous, and digestive systems were the most frequently affected, without differences between groups. Treatment was discontinued in 31/320 (9.7%) patients without differences between groups. However, ADR-related discontinuations occurred more frequently in adults than in children (OR = 5.5, 95% CI = 1.5 to 24). Our study supports the safety of NF for ChD treatment. Delaying NF treatment due to safety concerns does not seem to be supported by the evidence. (This study has been registered in ClinicalTrials.gov under identifier NCT04274101.).
| S-EPMC7849004 | biostudies-literature
Project description:Chagas disease (CD) is a parasitic zoonosis endemic in Central and South America affecting nearly 10 million people, with 100 million people at high risk of contracting the disease. Treatment is only effective when received at the early stages of the disease and it involved two drugs (nifurtimox (NFX) and benznidazole (BNZ)). Both treatments require multiple daily administrations of high doses, suffer from variable efficacy and insufficient efficacy in chronic CD, many side effects, and a very long duration of treatment that results in poor compliance, while combined available therapies that lead to reduced duration of treatment are not available and polypharmacy reduces compliance and increases the cost further. Here we present self-nanoemulsified drug delivery systems (SNEDDS) able to produce easily scalable combined formulations of NFX and BNZ that can allow for tailoring of the dose and can be easily converted to oral solid dosage form by impregnation on mesoporous silica particles. SNEDDS demonstrated an enhanced solubilisation capacity for both drugs as demonstrated by flow-through studies and in vitro lipolysis studies. High loading of SNEDDS to Syloid 244 and 3050 silicas (2:1 w/w) allowed clinically translatable amounts of both NFX and BNZ to be loaded. Tablets prepared from NFX-BNZ combined SNEDDS loaded on Syloid 3050 silicas demonstration near complete dissolution in the flow through cell apparatus compared to NFX and BNZ commercial tablets respectively (Lampit® and Rochagan®). NFX-BNZ-SNEDDS demonstrated nanomolar efficacy in epimastigotes and amastigotes of T. cruzi with acceptable selectivity indexes and demonstrated enhanced survival and reduced parasitaemia in acute murine experimental models of CD. Thus, the results presented here illustrate the ability for an easily scalable and personalised combination oral therapy prepared from GRAS excipients, enabling treatment access worldwide for the treatment of CD.
| S-EPMC9504116 | biostudies-literature
Project description:BackgroundTreatment with nifurtimox (NF) for Chagas disease is discouraged during breast-feeding because no information on NF transfer into breast milk is available. NF is safe and effective for paediatric and adult Chagas disease. We evaluated the degree of NF transfer into breast milk in lactating women with Chagas disease.Patients and methodsProspective study of a cohort of lactating women with Chagas disease. Patients were treated with NF for 1 month. NF was measured in plasma and milk by high performance liquid chromatography (HPLC). Breastfed infants were evaluated at admission, 7th and 30th day of treatment (and monthly thereafter, for 6 months).ResultsLactating women with chronic Chagas disease (N = 10) were enrolled (median age 28 years, range 17-36). Median NF dose was 9.75 mg/kg/day three times a day (TID). Six mothers had mild adverse drug reactions (ADRs), but no ADRs were observed in any of the breastfed infants. No interruption of breastfeeding was observed. Median NF concentrations were 2.15 mg/L (Inter quartil range (IQR) 1.32-4.55) in milk and 0.30 mg/L (IQR 0.20-0.95) in plasma. Median NF milk/plasma ratio was 16 (range 8.75-30.25). Median relative infant NF dose (assuming a daily breastmilk intake of 150 mL/kg/day) was 6.7% of the maternal dose/kg/day (IQR 2.35-7.19%).ConclusionsThe low concentrations of NF in breast milk and the normal clinical evaluation of the breastfed babies imply that maternal NF treatment for Chagas disease during breastfeeding is unlikely to lead to clinically relevant exposures in the breastfed infants.Trial registrationClinical trial registry name and registration number: ClinicalTrials.gov NCT01744405.
| S-EPMC6711540 | biostudies-literature
Project description:BackgroundNifurtimox is 1 of only 2 medications available for treating Chagas disease (CD) and currently the only drug available in the United States, but its safety and tolerance have not been extensively studied. This is the first study to evaluate tolerance of nifurtimox in US patients with CD.MethodsThis investigation assessed side effects in a sample of 53 patients with CD, all Latin American immigrants, who underwent treatment with nifurtimox (8-10 mg/kg in 3 daily doses for 12 weeks) from March 2008 to July 2012. The frequency and severity of adverse events (AEs) was recorded.ResultsA total of 435 AEs were recorded; 93.8% were mild, 3.0% moderate, and 3.2% severe. Patients experienced a mean of 8.2 AEs; the most frequent were anorexia (79.2%), nausea (75.5%), headache (60.4%), amnesia (58.5%), and >5% weight loss (52.8%). Eleven patients (20.8%) were unable to complete treatment. Experiencing a moderate or severe AE (odds ratio [OR], 3.82; P < .05) and Mexican nationality (OR, 2.29; P < .05) were significant predictors of treatment discontinuation, but sex and cardiac progression at baseline were not. Patients who did not complete treatment experienced nearly 3 times more AEs per 30-day period (P = .05).ConclusionsNifurtimox produces frequent side effects, but the majority are mild and can be managed with dose reduction and/or temporary suspension of medication. The high frequency of gastrointestinal symptoms and weight loss mirrors results from prior investigations. Special attention should be paid during the early stages of treatment to potentially severe symptoms including depression, rash, and anxiety.
| S-EPMC5036918 | biostudies-literature
Project description:Children requiring cortisol replacement therapy are often prescribed hydrocortisone doses of 2.5?mg, but as this is commercially unavailable 10?mg tablets, with functional break lines, are split commonly in an attempt to deliver the correct dose. This study aimed to determine the dose variation obtained from quartered hydrocortisone tablets when different operators performed the splitting procedure and to ascertain whether better uniformity could be attained from mini-tablets as an alternative formulation.Hydrocortisone 10?mg tablets were quartered by four different operators using a standard pill splitter. Hydrocortisone 2.5?mg mini-tablets (3?mm diameter) were formulated using a wet granulation method and manufactured using a high-speed rotary press simulator. The weight and content uniformity of the quartered tablets and mini-tablets were assessed according to pharmacopoeial standards. The physical strength and dissolution profiles of the mini-tablets were also determined.More than half of all quartered 10?mg tablets were outside of the ±10% of the stated US Pharmacopoeia hydrocortisone content (mean 2.34?mg, SD 0.36, coefficient of variation (CV) 15.18%) and more than 40% of the quartered tablets were outside the European Pharmacopoeia weight variation. Robust mini-tablets (tensile strengths of >4?MPa) were produced successfully. The mini-tablets passed the pharmacopoeial weight and content uniformity requirements (mean 2.54?mg, SD 0.04, CV 1.72%) and drug release criteria during in vitro dissolution testing.This study confirmed that quartering 10?mg hydrocortisone tablets produces unacceptable dose variations and that it is feasible to produce 3?mm mini-tablets containing more accurate doses for paediatric patients.
| S-EPMC5843003 | biostudies-literature