scholarly journals Pharmacometric analysis of tribendimidine mono- and combination therapies to achieve high cure rates in patients with hookworm infections

2020 ◽  
Author(s):  
Janneke M. Brussee ◽  
Anna Neodo ◽  
Jessica D. Schulz ◽  
Jean T Coulibaly ◽  
Marc Pfister ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Treatment Strategy ◽  
Maximum Effect ◽  
Response Analysis ◽  
Population Pharmacokinetic ◽  
Combination Therapies ◽  
Primary And Secondary Metabolites ◽  
Cure Rates ◽  
Hookworm Infections ◽  
Oxantel Pamoate

To treat hookworm infections, pharmacotherapy has been only moderately successful and drug resistance is a threat. Therefore, novel treatment options including combination therapies should be considered, in which tribendimidine could play a role. Our aims were to (i) characterize the pharmacokinetics of tribendimidine's metabolites in adolescents receiving tribendimidine monotherapy, or a combination with ivermectin or oxantel pamoate, (ii) evaluate possible drug-drug interactions (DDI), (iii) link exposure to response, aiming to (iv) identify a treatment strategy associated with high efficacy, i.e. >90% cure rates (CRs), utilizing model-based simulations. A population pharmacokinetic model was developed for tribendimidine's primary and secondary metabolites dADT and adADT in 54 hookworm-positive adolescents, with combination therapy evaluated as possible covariate. Subsequently, an exposure-response analysis was performed utilizing CRs as response markers. Simulations were performed to identify a treatment strategy to achieve >90% CRs. A two-compartmental model best described metabolite disposition. No pharmacokinetic DDI was identified with ivermectin or oxantel pamoate. All participants receiving tribendimidine plus ivermectin were cured. For the monotherapy and combination with oxantel pamoate arm, Emax models adequately described the correlation between dADT exposure and probability to be cured, with a required exposure to achieve 50% of maximum effect of 39.6 and 15.6 nmol/mL*h, respectively. Based on our simulations an unrealistically high monotherapy tribendimidine dose would be necessary to achieve CRs >90%, while combination therapy with ivermectin would meet this desired target product profile. Further clinical studies should be launched to develop this combination for the treatment of hookworm and other helminth infections.

scholarly journals Population pharmacokinetics and exposure-response analysis of tribendimidine to improve treatment for children with hookworm infection

2020 ◽  
Author(s):  
Janneke M. Brussee ◽  
Noemi Hiroshige ◽  
Anna Neodo ◽  
Jean T. Coulibaly ◽  
Marc Pfister ◽  
...  
Keyword(s):  
Children And Adolescents ◽  
Treatment Strategy ◽  
Response Analysis ◽  
Hookworm Infection ◽  
Primary Metabolite ◽  
School Aged Children ◽  
Improve Treatment ◽  
Exposure Response ◽  
Cure Rates ◽  
Hookworm Infections

Tribendimidine has been successful in treating hookworm infections and may serve as alternative to albendazole should resistance arise. Our aims were to (i) characterize the pharmacokinetics (PK) of tribendimidine's primary metabolite deacetylated amidantel (dADT) and secondary metabolite, acetylated derivative of amidantel (adADT) in school-aged children and adolescents, (ii) link exposure to efficacy against hookworm, and (iii) evaluate whether tribendimidine pharmacotherapy in children could be further improved. First, a population PK model was developed based on dried-blood-spot samples collected in 155 school-aged children and adolescents with hookworm infections, following tribendimidine doses ranging from 100-400 mg. Second, an exposure-response analysis was conducted to link the active metabolite dADT to cure rates (CRs) and egg reduction rates (ERRs). Third, simulations were performed to identify a treatment strategy associated with >90% CRs. A two-compartmental model with transit compartments describing observed delay in absorption adequately described PK data of dADT and adADT. Allometric scaling was included to account for growth and development. The absorption rate was 56% lower with 200-mg tablets compared with 50 mg tablets, while the extent of absorption remained unaffected. The identified Emax models linking dADT exposure to ERRs and CRs showed shallow curves, as increasing exposure leads to marginal efficacy increase. Combination therapy should be considered as a 12-fold higher dose would be needed to achieve 95% ERRs and CRs >90% with tribendimidine alone. Further studies are warranted to evaluate safety of higher tribendimidine doses and combination therapies with other anthelmintic agents to improve treatment strategy for children with hookworm infection.

scholarly journals Semi-mechanistic pharmacokinetic and pharmacodynamic modelling of piperaquine in a volunteer infection study with Plasmodium falciparum blood-stage malaria

2021 ◽  
Author(s):  
Thanaporn Wattanakul ◽  
Mark Baker ◽  
Joerg Mohrle ◽  
Brett McWhinney ◽  
Richard M. Hoglund ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Combination Therapy ◽  
Multidrug Resistant ◽  
Pharmacodynamic Model ◽  
Blood Stage ◽  
Maximum Effect ◽  
Combination Therapies ◽  
Triple Combination Therapy ◽  
The Impact ◽  
Parasite Dynamics

Dihydroartemisinin-piperaquine is a recommended first-line artemisinin combination therapy for falciparum malaria. Piperaquine is also under consideration for other antimalarial combination therapies. The aim of this study was to develop a pharmacokinetic-pharmacodynamic model that could be used to optimize the use of piperaquine in new antimalarial combination therapies. The pharmacokinetic-pharmacodynamic model was developed using data from a previously reported dose-ranging study where 24 healthy volunteers were inoculated 1,800 blood-stage Plasmodium falciparum parasites. All volunteers received a single oral dose of piperaquine (960 mg, 640 mg, or 480 mg) on day 7 or day 8 after parasite inoculation in separate cohorts. Parasite densities were measured by qPCR, and piperaquine levels were measured in plasma samples. We used nonlinear mixed-effect modelling to characterize the pharmacokinetic properties of piperaquine and the parasite dynamics associated with piperaquine exposure. Pharmacokinetics of piperaquine was described by a three-compartment disposition model. A semi-mechanistic parasite dynamics model was developed to explain maturation of parasites, sequestration of mature parasites, synchronicity of infections, and multiplication of parasites, as seen in natural clinical infections with falciparum malaria. Piperaquine-associated parasite killing was estimated using a maximum effect (Emax) function. Treatment simulations (i.e. 3-day oral dosing of dihydroartemisinin-piperaquine) indicated that to be able to combat multidrug resistant infections, an ideal additional drug in a new antimalarial triple-combination therapy should have a parasite reduction ratio of ≥102 per life cycle (38.8 h) with a duration of action of ≥ 2 weeks. The semi-mechanistic pharmacokinetic-pharmacodynamic model described here offers the potential to be a valuable tool to assess and optimize current and new antimalarial drug combinations therapies containing piperaquine, and the impact of these therapies on killing multidrug resistant infections.

Projecting the long-term benefits of single pill combination therapy for patients with hypertension in five countries

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
C Borghi ◽  
J.G Wang ◽  
A.V Rodionov ◽  
M Rosas ◽  
I.S Sohn ◽  
...  
Keyword(s):  
Combination Therapy ◽  
South Korea ◽  
Health Outcomes ◽  
Clinical Outcomes ◽  
Funding Source ◽  
Combination Therapies ◽  
Private Company ◽  
Treatment Pathways ◽  
Single Pill ◽  
The Impact

Abstract Background It is well established that single pill combination (SPC) therapies have the potential to improve patient adherence versus multi-pill regimens, thereby improving blood pressure control and clinical outcomes in populations with hypertension. Purpose To develop a microsimulation model, capturing different treatment pathways, to project the impact on clinical outcomes of using single pill combination therapies for the management of hypertension in five countries (Italy, Russia, China, South Korea and Mexico). Methods The model was designed to project health outcomes between 2020 and 2030 for populations with hypertension managed according to four different treatment pathways: current treatment practices [CTP], single drug with dosage titration first then sequential addition of other agents [start low and go slow, SLGS], free choice combination with multiple pills [FCC] and combination therapy in the form of a single pill [SPC]. Model inputs were derived from Global Burden of Disease 2017 dataset, including demographics, health status/risk factors, transition probabilities and treatment attributes/healthcare utilization, and the model incorporated real-world challenges to healthcare delivery such as access to care, SBP measurement error, adherence and therapeutic inertia. Simulated outcomes of mortality, incidence of chronic kidney disease (CKD), stroke and ischemic heart disease (IHD), and disability-adjusted life years (DALYs) due to these conditions were estimated for population of 1,000,000 simulated patients for each treatment pathway and country. Results SPC therapy was projected to improve health outcomes over SLGS, FCC and CTP over 10 years in all five countries. SPC was forecast to reduce mortality by 5.4% (Italy), 4.9% (Russia), 4.5% (China), 2.3% (South Korea) and 3.6% (Mexico) versus CTP and showed greater projected reductions in mortality than SLGS and FCC. DALYs were projected to be reduced with SPC therapy by between 5.7% (Italy) and 2.2% (South Korea) compared with CTP and reductions in the incidence of clinical events were also projected with SPC therapy, with decreases in the range of 11.5% (Italy) to 4.9% (South Korea) versus CTP. Conclusions Ten-year projections of clinical outcomes associated with different anti-hypertensive treatment pathways in five countries indicated that both combination therapies (FCC and SPC) are likely to reduce the disease burden of hypertension compared with conventional management approaches, with SPC showing the greatest overall benefits due to improved adherence. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Sanofi, Gentilly, France

scholarly journals Treatment patterns, healthcare resource utilization, and healthcare costs among patients with pulmonary arterial hypertension in a real-world US database

2018 ◽  
Vol 9 (1) ◽  
pp. 204589401881629 ◽  
Author(s):  
Sean Studer ◽  
Michael Hull ◽  
Janis Pruett ◽  
Eleena Koep ◽  
Yuen Tsang ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Combination Therapy ◽  
Arterial Hypertension ◽  
Resource Utilization ◽  
Real World ◽  
Healthcare Resource ◽  
Healthcare Resource Utilization ◽  
Treatment Patterns ◽  
Combination Therapies ◽  
Pulmonary Arterial

Several new medications for pulmonary arterial hypertension (PAH) have recently been introduced; however, current real-world data regarding US patients with PAH are limited. We conducted a retrospective administrative claims study to examine PAH treatment patterns and summarize healthcare utilization and costs among patients with newly diagnosed PAH treated in US clinical practice. Patients newly treated for PAH from 1 January 2010 to 31 March 2015 were followed for ≥12 months. Patient characteristics, treatment patterns, healthcare resource utilization, and costs were described. Adherence (proportion of days covered), persistence (months until therapy discontinuation/modification), and the probability of continuing the index regimen were analyzed by index regimen cohort (monotherapy versus combination therapy). Of 1637 eligible patients, 93.8% initiated treatment with monotherapy and 6.2% with combination therapy. The most common index regimen was phosphodiesterase type 5 inhibitor (PDE-5I) monotherapy (70.0% of patients). A total of 581 patients (35.5%) modified their index regimen during the study. Most patients (55.4%) who began combination therapy did so on or within six months of the index date. Endothelin receptor agonists (ERAs) and combination therapies were associated with higher adherence than PDE-5Is and monotherapies, respectively. Healthcare utilization was substantial across the study population, with costs in the combination therapy cohort more than doubling from baseline to follow-up. The majority of patients were treated with monotherapies (most often, PDE-5Is), despite combination therapies and ERAs being associated with higher medication adherence. Index regimen adjustments occurred early and in a substantial proportion of patients, suggesting that inadequate clinical response to monotherapies may not be uncommon.

scholarly journals Pharmacokinetics-Pharmacodynamics of Gatifloxacin in a Lethal Murine Bacillus anthracis Inhalation Infection Model

2007 ◽  
Vol 51 (12) ◽  
pp. 4351-4355 ◽  
Author(s):  
Paul G. Ambrose ◽  
Alan Forrest ◽  
William A. Craig ◽  
Chistopher M. Rubino ◽  
Sujata M. Bhavnani ◽  
...  
Keyword(s):  
Bacillus Anthracis ◽  
Survival Data ◽  
Sensitivity Analyses ◽  
Maximum Effect ◽  
Infection Model ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Models ◽  
Concentration Time ◽  
Dosing Regimens ◽  
Adults And Children

ABSTRACT We determined the pharmacokinetic-pharmacodynamic (PK-PD) measure most predictive of gatifloxacin efficacy and the magnitude of this measure necessary for survival in a murine Bacillus anthracis inhalation infection model. We then used population pharmacokinetic models for gatifloxacin and simulation to identify dosing regimens with high probabilities of attaining exposures likely to be efficacious in adults and children. In this work, 6- to 8-week-old nonneutropenic female BALB/c mice received aerosol challenges of 50 to 75 50% lethal doses of B. anthracis (Ames strain, for which the gatifloxacin MIC is 0.125 mg/liter). Gatifloxacin was administered at 6- or 8-h intervals beginning 24 h postchallenge for 21 days, and dosing was designed to produce profiles mimicking fractionated concentration-time profiles for humans. Mice were evaluated daily for survival. Hill-type models were fitted to survival data. To identify potentially effective dosing regimens, adult and pediatric population pharmacokinetic models for gatifloxacin and Monte Carlo simulation were used to generate 5,000 individual patient exposure estimates. The ratio of the area under the concentration-time curve from 0 to 24 h (AUC0-24) to the MIC of the drug for the organism (AUC0-24/MIC ratio) was the PK-PD measure most predictive of survival (R 2 = 0.96). The 50% effective dose (ED50) and the ED90 and ED99 corresponded to AUC0-24/MIC ratios of 11.5, 15.8, and 30, respectively, where the maximum effect was 97% survival. Simulation results indicate that a daily gatifloxacin dose of 400 mg for adults and 10 mg/kg of body weight for children gives a 100% probability of attaining the PK-PD target (ED99). Sensitivity analyses suggest that the probability of PK-PD target attainment in adults and children is not affected by increases in MICs for strains of B. anthracis to levels as high as 0.5 mg/liter.

scholarly journals A rational pharmacotherapeutic study of comparative safety among topical anti-acne 1% nadifloxacin monotherapy, 0.1% adapalene monotherapy, 0.025% tretinoin monotherapy, 1% nadifloxacin and 0.1% adapalene combination therapy and 1% nadifloxacin and 0.025% tretinoin combination therapy, in mild to moderate acne vulgaris, in tertiary care hospitals

2019 ◽  
Vol 8 (9) ◽  
pp. 1959
Author(s):  
Moumita Hazra
Keyword(s):  
Adverse Effects ◽  
Combination Therapy ◽  
Acne Vulgaris ◽  
Tertiary Care ◽  
Skin Irritation ◽  
Combination Therapies ◽  
Global Alliance ◽  
Topoisomerase Iv ◽  
Significant Difference ◽  
Anti Inflammatory

Background: Topical adapalene and tretinoin, are comedolytic, anti-comedogenic and anti-inflammatory, on RAR (α, β, γ) receptors binding. Adapalene enables quicker follicular penetration, by lesser anti-AP-1 (c-Jun, c-Fos) and no CRBPII mRNA actions, causing chemical stability, lipophilicity and less photo-lability, producing lesser photosensitivity and no skin irritation, unlike tretinoin; wherein reducible by overnight application and combination therapy, slow-release polymers or emollients, respectively. Topical nadifloxacin is bactericidal, anti-inflammatory and comedolytic, with inhibitory effect on DNA gyrase, DNA topoisomerase IV and IL-1α, IL-6, IL-8. The Global Alliance to Improve Outcomes in Acne Guidelines recommend synergistic and additive combination therapies, which enhance therapeutic efficacy and reduce adverse effects. Due to inadequacy of data, this study was conducted, to compare the safety among topical anti-acne monotherapies and combination therapies, and to easily detect any adverse effect producing component in the topical combination therapy.Methods: In this multi-centre, prospective, randomised, open-labelled, comparative study, groups A, B, C, D and E (20 patients each), applied topical 1% nadifloxacin monotherapy, 0.1% adapalene monotherapy, 0.025% tretinoin monotherapy, 1% nadifloxacin and 0.1% adapalene combination therapy and 1% nadifloxacin and 0.025% tretinoin combination therapy, respectively, over their facial mild to moderate acne lesions, once daily overnight; and adverse effects, like erythema, scaling, dryness, prutitus, burning, or stinging, were assessed on 0, 15, 30, 60, 90 days and follow-ups, by Local Irritation Scale.Results: In all 5 groups, no adverse effects were observed, with no statistically significant difference among the observations.Conclusions: The therapies were well tolerated and safe among all 5 groups.

scholarly journals Screening a library of FDA-approved and bioactive compounds for antiviral activity against SARS-CoV-2

2020 ◽  
Author(s):  
Scott B. Biering ◽  
Erik Van Dis ◽  
Eddie Wehri ◽  
Livia H. Yamashiro ◽  
Xammy Nguyenla ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Combination Therapy ◽  
Global Health ◽  
Antiviral Activity ◽  
Drug Repurposing ◽  
Rapid Identification ◽  
Screening Strategy ◽  
Combination Therapies ◽  
Pulmonary Epithelial Cells ◽  
Compound Screening

AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), has emerged as a major global health threat. The COVID-19 pandemic has resulted in over 80 million cases and 1.7 million deaths to date while the number of cases continues to rise. With limited therapeutic options, the identification of safe and effective therapeutics is urgently needed. The repurposing of known clinical compounds holds the potential for rapid identification of drugs effective against SARS-CoV-2. Here we utilized a library of FDA-approved and well-studied preclinical and clinical compounds to screen for antivirals against SARS-CoV-2 in human pulmonary epithelial cells. We identified 13 compounds that exhibit potent antiviral activity across multiple orthogonal assays. Hits include known antivirals, compounds with anti-inflammatory activity, and compounds targeting host pathways such as kinases and proteases critical for SARS-CoV-2 replication. We identified seven compounds not previously reported to have activity against SARS-CoV-2, including B02, a human RAD51 inhibitor. We further demonstrated that B02 exhibits synergy with remdesivir, the only antiviral approved by the FDA to treat COVID-19, highlighting the potential for combination therapy. Taken together, our comparative compound screening strategy highlights the potential of drug repurposing screens to identify novel starting points for development of effective antiviral mono- or combination therapies to treat COVID-19.

Cryo, Hyper or Both? Investigating Combination Cryo/Hyperthermia in the Dorsal Skin Flap Chamber

2000 ◽  
Author(s):  
Nathan E. Hoffmann ◽  
Bo H. Chao ◽  
John C. Bischof
Keyword(s):  
Combination Therapy ◽  
Thermal History ◽  
Standard Treatment ◽  
Tissue Injury ◽  
Skin Flap ◽  
Dorsal Skin ◽  
Combination Therapies ◽  
Disease Treatment ◽  
Copenhagen Rat

Abstract Combination therapies have been investigated as a mean to increase efficacy of disease treatment. For example, combinations such as radiation and chemotherapy, surgery and chemotherapy, and two different chemotherapies have become standard treatment for most cancers. Current theories suggest that vascular-mediated injury is an important mechanism of cryosurgical (reviewed in Gage and Baust (1998)) and hyperthermic destruction (Badylak et al., 1985; Dudar and Jain, 1984) in the treatment of solid tumors. These techniques appear complementary. Freezing creates vascular damage and promotes stasis within the vessels (Rabb et al., 1974), whereas hyperthermia creates cell and vascular destruction more effectively with a compromised vasculature (Shakil et al., 1999). Thus, in this study, we investigated the effect of combining these therapies on the vascular and tissue injury from the two therapies. We chose the dorsal skin flap chamber (DSFC) implanted in the Copenhagen rat as the cryosurgical model for this study. This in vivo freezing model allowed us to monitor thermal history and investigate both vascular and tissue injury in response to the combination therapy.

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