scholarly journals How long will treatment guidelines for TB continue to overlook variability in drug exposure?

2019 ◽  
Vol 74 (11) ◽  
pp. 3274-3280
Author(s):  
Morris Muliaditan ◽  
Oscar Della Pasqua
Keyword(s):  
Dose Regimen ◽  
Drug Exposure ◽  
Treatment Guidelines ◽  
Systemic Exposure ◽  
Standard Of Care ◽  
Fixed Dose ◽  
Pharmacokinetic Parameters ◽  
Long Term Outcome ◽  
Tb Treatment ◽  
Dosing Regimens

Abstract Background Despite wide clinical acceptance, the use of weight-banded dosing regimens for the treatment of TB in adults has been defined on an empirical basis. The potential impact of known covariate factors on exposure to different drugs has not been taken into account. Objectives To evaluate the effect of demographic factors on the exposure to standard of care drugs after weight-banded dosing, as currently recommended by TB treatment guidelines. In addition, we aim to identify alternative dosing regimens that ensure comparable systemic exposure across the overall patient population. Methods Clinical trial simulations were performed to assess the differences in systemic exposure in a cohort of virtual patients. Secondary pharmacokinetic parameters were used to evaluate the adequacy of each regimen along with the percentage of patients achieving predefined thresholds. Results Our results show that patients weighing less than 40 kg are underexposed relative to patients with higher body weight. The opposite trend was observed following a crude weight band-based dosing regimen with 50 kg as the cut-off point. Simulations indicate that a fixed-dose regimen based on three (<40 kg), four (40–70 kg) or five (>70 kg) tablets of 150 mg rifampicin, 75 mg isoniazid, 400 mg pyrazinamide and 275 mg ethambutol reduces variability in exposure, increasing the overall probability of favourable long-term outcome across the population. Conclusions These findings suggest the need to revisit current guidelines for the dose of standard of care drugs for TB treatment in adults. The proposed fixed-dose regimen should be considered in future clinical trials.

scholarly journals ANALYSIS OF TUBERCULOSIS TREATMENT SUITABILITY AND THE DRUG SUPERVISOR’S ROLE IN A COMMUNITY HEALTH CENTER IN PADEMANGAN SUBDISTRICT, NORTH JAKARTA

2019 ◽  
pp. 272-276
Author(s):  
CITRA FEBRIONY ◽  
PURWANTYASTUTI . ◽  
MEANALDI RASMIN ◽  
VIVIAN SOETIKNO
Keyword(s):  
Side Effects ◽  
Community Health ◽  
Health Center ◽  
Treatment Guidelines ◽  
Community Health Center ◽  
Intervention Group ◽  
Treatment Compliance ◽  
Fixed Dose ◽  
Control Group ◽  
Tb Treatment

Objective: Appropriate tuberculosis (TB) treatment guidelines are one of the many factors that influence the success of TB treatment. The patient’sdrug supervisor is a functional role that is part of the directly observed treatment short course, a program to support the success of TB treatment.The aim of this study was to analyze the TB treatment suitability in a community health center and the benefit of treatment compliance supervisionby the patient’s designated drug supervisor.Methods: We conducted a cross-sectional study in the Community Health Center of Pademangan subdistrict, North Jakarta, involving 205 subjects toanalyze appropriate fixed-dose combination (FDC) anti-TB drug administration and an experimental study involving 23 control group TB patients and23 intervention group TB patients to assess the benefit of supervision by each patient’s drug supervisor.Results: The association of FDC anti-TB drug side effects with the success of TB treatment was not statistically significant (p=0.173). There wasan increase in drug supervisor knowledge of 8.6% in the intervention group and 13% in the control group. There was no statistically significantassociation between the knowledge of the drug supervisor and the 2nd month (p=0.575) and the 6th month of sputum treatment.Conclusion: Minor side effects of FDC anti-TB drug did not affect the success of TB treatment; therefore, treatment was continued if these adverseevents occurred. There were no correlations between the drug supervisor knowledge level with medication compliance or with sputum conversion(months 2 and 6).

An evaluation of the drug interaction potential of netupitant with palonosetron, dexamethasone, and oral contraceptives.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e19532-e19532
Author(s):  
Jan Vouis ◽  
Anders Henriksson ◽  
Wolfgang Timmer ◽  
Selma Calcagnile ◽  
Giorgia Rossi
Keyword(s):  
Drug Interaction ◽  
Oral Contraceptives ◽  
Systemic Exposure ◽  
Fixed Dose ◽  
Pharmacokinetic Parameters ◽  
Dependent Manner ◽  
Dose Combination ◽  
Neurokinin 1 ◽  
Practice Methods ◽  
New Generation

e19532 Background: Netupitant (NETU) is a highly selective neurokinin 1 receptor antagonist (NK1 RA) developed to provide protection from nausea and vomiting in patients undergoing emetogenic chemotherapy. Three individual studies were aimed at determining NETU effect on the metabolism of the new generation 5-HT3 RA palonosetron (PALO), dexamethasone (DEX) and oral contraceptives which may be coadministered in clinical practice. Methods: Two 3-way crossover studies to determine the interaction between NETU (450 mg, day 1) and PALO (0.75 mg PO, day 1), and between NETU (100 mg, 300 mg or 450 mg PO, day 1) and DEX (20 mg PO, day 1; 8 mg BID PO, days 2-4), were performed in 18 and 25 healthy subjects, respectively. The study investigating the effect of NETU/PALO (300 mg/0.5 mg PO) as a fixed dose combination on the PK of oral contraceptives ethinylestradiol and levonorgestrel (60 μg/300 μg) was a 2-way crossover trial of 24 healthy women. Serial blood samples were collected over the course of the three studies and pharmacokinetic parameters were determined for all analytes. Results: There were no significant pharmacokinetic interactions between NETU and PALO. DEX mean AUC and Cmax increased respectively, by 1.7 and 1.1 fold on day 1 and by 2.4 and 1.7 fold on day 4 when coadministered with NETU. NETU was shown to increase exposure to DEX in a dose-dependent manner. The combination of NETU/PALO did not significantly affect exposure to ethinylestradiol; systemic exposure to levonorgestrel increased by 40%, a level that is not considered clinically relevant. Conclusions: A relevant drug interaction was seen between NETU and DEX and therefore dose reductions are recommended for DEX when administered with NETU. This drug interaction is likely due to inhibition of CYP3A4 by NETU. No interaction was clinically relevant between NETU and PALO, or between NETU/PALO and ethinylestradiol and levonorgestrel. Treatments were well-tolerated in all studies.

scholarly journals Pharmacokinetics of Dihydroartemisinin and Piperaquine in Pregnant and Nonpregnant Women with Uncomplicated Falciparum Malaria

2011 ◽  
Vol 55 (12) ◽  
pp. 5500-5506 ◽  
Author(s):  
Marcus J. Rijken ◽  
Rose McGready ◽  
Aung Phae Phyo ◽  
Niklas Lindegardh ◽  
Joel Tarning ◽  
...  
Keyword(s):  
Pregnant Women ◽  
Falciparum Malaria ◽  
Half Life ◽  
Drug Exposure ◽  
Venous Blood ◽  
Uncomplicated Falciparum Malaria ◽  
Fixed Dose ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Population Pharmacokinetic Modeling

ABSTRACTDihydroartemisinin-piperaquine is a fixed-dose artemisinin-based combination treatment. Some antimalarials have altered pharmacokinetics in pregnancy. Pregnant women in the 2nd or 3rd trimester and matched nonpregnant women with uncomplicated falciparum malaria were treated with a total of 6.4 mg/kg of body weight dihydroartemisinin and 51.2 mg/kg piperaquine once daily for 3 days. Venous blood samples were drawn at prespecified time points over 9 weeks. Plasma dihydroartemisinin and piperaquine concentrations were analyzed by liquid chromatography-mass spectrometry. Piperaquine and dihydroartemisinin pharmacokinetics were well described. There were no significant differences in total piperaquine exposure (P= 0.80) or drug exposure during the terminal elimination phase (72 h to infinity) (P= 0.64) between the two groups. The apparent volume of distribution of piperaquine was significantly smaller (602 liters/kg versus 877 liters/kg) in pregnant women than in nonpregnant women (P= 0.0057), and the terminal elimination half-life was significantly shorter (17.8 days versus 25.6 days;P= 0.0023). Dihydroartemisinin exposure after the first dose was significantly lower (844 h × ng/ml versus 1,220 h × ng/ml,P= 0.0021) in pregnant women, but there were no significant differences in total dihydroartemisinin exposure or maximum concentrations between the two groups. There were no significant differences in any pharmacokinetic parameters between the second and third trimester. These results obtained through noncompartmental analysis suggest that in the treatment of falciparum malaria, there are no clinically important differences in the pharmacokinetics of dihydroartemisinin or piperaquine between pregnant and nonpregnant women. However, a more detailed analysis using population pharmacokinetic modeling is needed to fully investigate the differences found for some of the pharmacokinetic parameters, such as the terminal half-life.

scholarly journals Busulfan pharmacokinetics using a single daily high-dose regimen in children with acute leukemia

Blood ◽  
1994 ◽  
Vol 84 (7) ◽  
pp. 2357-2362 ◽  
Author(s):  
PJ Shaw ◽  
CE Scharping ◽  
RJ Brian ◽  
JW Earl
Keyword(s):  
Acute Leukemia ◽  
Dose Regimen ◽  
Peak Plasma ◽  
Area Under The Curve ◽  
Systemic Exposure ◽  
Single Daily Dose ◽  
Pharmacokinetic Parameters ◽  
High Dose ◽  
Peak Plasma Level ◽  
Daily Dose

Abstract The pharmacokinetics of busulfan, given as a single daily dose (either 4 mg/kg or 150 mg/m2), was determined in 22 children undergoing bone marrow transplantation for acute leukemia. The single daily dose regimen showed similar pharmacokinetics to previously reported regimens of 4 x 1 mg/kg, except for fourfold higher mean peak plasma levels and negligible trough levels. Daily systemic exposure for single dose regimens based on weight (4 mg/kg) or surface area (150 mg/m2), respectively were very similar to regimens of (4 x 1 mg/kg) or (4 x 37.5 mg/m2). Dose (milligrams per kilogram), peak plasma level, and area under the curve (AUC) were all higher in 12 children treated with 150 mg/m2 busulfan than in 9 children treated with 4 mg/kg. AUC was age dependent for the 4 mg/kg dose but not for the 150 mg/m2 dose. The use of a 150 mg/m2 dose allows escalation of the dose above 4 mg/kg, eliminating the tendency for younger children to receive lower systemic exposure. Little toxicity was observed in this study. Clearance and distribution volume correlated negatively with age, and AUC correlated positively with dose (milligram per kilogram). Administration of busulfan as crushed rather than whole tablets reduced the delay time for appearance of busulfan in plasma but had no effect on absorption or other pharmacokinetic parameters.

Therapeutic Drug Monitoring: Role for a Pharmacist in Multidisciplinary Antiretroviral Management

2005 ◽  
Vol 18 (4) ◽  
pp. 310-321
Author(s):  
Judianne C. Slish ◽  
Linda M. Catanzaro ◽  
Olanrewaju Okusanya ◽  
Lisa M. Demeter ◽  
Mary Albrecht ◽  
...  
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Drug Monitoring ◽  
Drug Exposure ◽  
Treatment Guidelines ◽  
Management Strategies ◽  
Additional Patient ◽  
Fixed Dose ◽  
Therapeutic Drug ◽  
Multiple Drug ◽  
Clinical Tool

The current treatment guidelines for HIV pharmacotherapy recommend combinations of antiretrovirals (ARVs) to achieve optimal suppression of HIV replication. However, the initiation and long-term management of ARV therapy in a patient is often complicated by variable medication adherence, complex medication use with multiple drug interactions, the occurrence of drug toxicity, and drug therapy for comorbid conditions that require additional patient education and laboratory monitoring. For these reasons, the inclusion of a well-trained pharmacist in multidisciplinary health system management strategies has been increasing. Furthermore, the use of fixed-dose ARVs is accompanied by considerable interpatient variation in pharmacokinetics yielding a range of drug exposures from any given ARV dose. One approach to overcoming this variable drug exposure is to use plasma concentration monitoring (eg, therapeutic drug monitoring [TDM]) as a clinical tool to adjust doses to achieve targeted concentration ranges, often in conjunction with HIV resistance tests. While data in support of TDM are emerging, the development of programs that include an HIV pharmaceutical care specialist and an adherence program with an integrated clinical pharmacology resource that can provide reliable TDM assays has been reported and provides the rationale for including pharmacists in the implementation of ARV TDM programs.

scholarly journals Feasibility of a Fixed-Dose Regimen of Pyrazinamide and Its Impact on Systemic Drug Exposure and Liver Safety in Patients with Tuberculosis

2012 ◽  
Vol 56 (11) ◽  
pp. 5442-5449 ◽  
Author(s):  
Tarjinder Sahota ◽  
Oscar Della Pasqua
Keyword(s):  
Dose Regimen ◽  
Drug Exposure ◽  
Therapeutic Agents ◽  
Fixed Dose ◽  
Population Pharmacokinetic ◽  
Target Exposure ◽  
Systemic Drug Exposure ◽  
The Impact ◽  
Systemic Drug ◽  
Novel Therapeutic

ABSTRACTHistorically, dosing regimens for the treatment of tuberculosis (TB) have been proposed in an empirical manner. Dose selection has often been the result of efficacy trials in which drugs were administered regardless of the magnitude of the effect of demographic factors on drug disposition. This has created challenges for the prescription of fixed-dose combinations with novel therapeutic agents. The objectives of this investigation were to evaluate the impact of body weight on the overall systemic exposure to pyrazinamide (PZA) and to assess whether the use of one fixed dose, without adjustment according to weight, would ensure target exposure and safety requirements across the overall patient population. Using a population pharmacokinetic model, simulation scenarios were explored based on population demographics from clinical trials in TB patients and on historical hepatotoxicity data. The systemic drug exposure (area under the concentration-time curve [AUC]), peak concentrations (the maximum concentration of drug in serum [Cmax]), the time above the MIC (t> MIC), and the risk of hepatotoxicity were evaluated for the current weight-banded regimen and compared to fixed doses under the assumption that pharmacokinetic differences are the primary drivers of toxicity. Evaluation of the standard weight banding reveals that more than 50% of subjects in the weight range of 45 to 55 kg remain below the proposed target exposure to PZA. In contrast, the use of a fixed 1,500-mg dose resulted in a lower proportion of subjects under the target value, with a 0.2% average overall increase in the risk of hepatotoxicity. Our results strongly support the use of a fixed-dose regimen for PZA in coformulation or combination with novel therapeutic agents.

scholarly journals 471 Pharmacokinetics of first and repeated dosing of non-irAE-inducing anti-CTLA-4 monoclonal antibody ONC-392 in advanced cancer patients

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A500-A500
Author(s):  
Hung-Yen Chou ◽  
Tianhong Li ◽  
Karen Kelly ◽  
Anthony Martinez ◽  
Stacy Joo ◽  
...  
Keyword(s):  
Drug Exposure ◽  
Safety Data ◽  
Systemic Exposure ◽  
Pharmacokinetic Parameters ◽  
Advanced Cancer Patients ◽  
Dose Ratio ◽  
Serum Samples ◽  
High Exposure ◽  
Apparent Lack ◽  
Repeated Dosing

BackgroundONC-392 preserves CTLA-4 recycling and thereby maintains its physiological immune tolerance checkpoint function while allowing more efficient and selective elimination of tumor-infiltrating regulatory T cells. The safety data in the first-in-human trial showed that ONC-392 is safe and well tolerated with no observed immunotherapy-related adverse events (irAE). Serum samples were used to determine pharmacokinetic parameters of ONC-392 to establish systemic drug exposure.MethodsSamples from the first and third dosing cycles were collected at predose and 0.5, 6, 24, 48, 192, 360, and 504 hours postdose. For other dosing cycles, predose and 0.5 hour postdose samples were collected. Serum ONC-392 concentrations were measured by ELISA and the PK parameters were analyzed under noncompartmental condition using linear trapezoidal method.ResultsSystemic exposure of ONC-392 is positively correlated to dosing concentration and number of doses. Mean Cmax and AUC 0–504hr values increase proportionately to dosing concentrations from 0.1mg/kg to 10mg/kg. Dose ratio in cycle 1 is 1:3:30:100. The mean cycle 1 Cmax and AUC 0–504hr ratios are 1:3.34:31.32:106.28 and 1:3.13:28.46:100.63 respectively. The Cmax in patients receiving one or more doses of ONC-392 at 3mg/kg is 89±16µg/mL. The Cmax in patients receiving one or more doses of ONC-392 at 10mg/kg is 259±55µg/mL. Inclusive of all dosing concentrations (0.1, 0.3, 1, 3, 10mg/kg) and cycles, Tmax is between 1.5–6 hours with one outlier observed at 24-hour postdose. The t½ range from 201 to 478 hours (8 - 20 days). The cycle 1 mean of t½ for 0.1, 0.3, 3, 10mg/kg dosing concentrations are 411.02, 359.25, 246.22, 355.01 hours respectively. A direct comparison between first and third cycle in the 3mg/kg dosing group confirms ONC-392 accumulation in repeated dosing. The trough levels (Cmin) in patients receiving one or multiple doses of ONC-392 at 3mg/kg and 10mg/kg are between 12–51µg/mL and 49–71µg/mL respectively. Lastly, inclusive of all dosing concentrations (0.1, 0.3, 1, 3, 10mg/kg) and cycles, MRT range from 307.91–655.04 hours, Vz range from 0.0305–0.0726 mg/(µg/mL), and Cl range from 0.000052–0.00019 mg/(µg/mL)/h.ConclusionsIntravenous infusion of ONC-392 provide adequate and dose-dependent exposure over extended period. Overall exposure is comparable or higher than those reported by others using different anti-CTLA-4 antibodies. The apparent lack of irAE in ONC-392 recipients despite the high exposure indicates intrinsic safety and tolerability of ONC-392.

Emergent Warfarin Reversal With Fixed-Dose 4-Factor Prothrombin Complex Concentrate

2020 ◽  
Vol 54 (11) ◽  
pp. 1090-1095
Author(s):  
Brianna Jansma ◽  
Josephine Montgomery ◽  
Scott Dietrich ◽  
Mark A. Mixon ◽  
Gary D. Peksa ◽  
...  
Keyword(s):  
Dose Regimen ◽  
Prothrombin Complex Concentrate ◽  
Package Insert ◽  
Cost Savings ◽  
Retrospective Chart Review ◽  
International Normalized Ratio ◽  
Fixed Dose ◽  
Potential Cost ◽  
Dosing Regimens ◽  
Warfarin Reversal

Background: Four-factor prothrombin complex concentrate (4FPCC) is used for emergent warfarin reversal, but dosing remains controversial. Following approval, further studies have evaluated a variety of fixed-dose regimens. The studies utilized lower doses as compared with package insert dosing and provided data in regard to efficacy, safety, and cost savings. Further data are needed, however, to determine which fixed-dose regimen provides optimal efficacy and safety for emergent warfarin reversal. Objectives: The purpose of this study is to evaluate the efficacy, safety, and cost-savings of a fixed-dose 4FPCC protocol. Methods: This multicentered, retrospective chart review of adult patients requiring 4FPCC for emergent warfarin reversal utilized a fixed-dose regimen of 1500 units. The 2 primary outcomes were the proportion of patients who achieved a post-4FPCC international normalized ratio (INR) of ≤1.5 and ≤2. Secondary outcomes included thrombotic events within 7 days of 4FPCC administration and survival to discharge. A cost analysis was also performed to identify potential cost savings. Results: Of the 64 patients included, 44 (68.8%) achieved a post-4FPCC INR ≤1.5, and 61 (95.3%) achieved a post-4FPCC INR ≤2.0. No thrombotic events were reported; 55 (85.9%) patients survived to hospital discharge. More than $1000 was saved per patient via utilization of the fixed-dose protocol. Conclusion and Relevance: A fixed-dose of 1500 units of 4FPCC successfully achieved a target INR of ≤1.5 in the majority of patients and resulted in no thrombotic events. This study adds to the data evaluating alternative 4FPCC dosing regimens in comparison to package insert recommended dosing.

scholarly journals Pharmacokinetic similarity demonstrated after crushing of the elbasvir/grazoprevir fixed-dose combination tablet for HCV infection

2020 ◽  
Vol 75 (9) ◽  
pp. 2661-2665
Author(s):  
Daniëlle W M Pijnenburg ◽  
Minou van Seyen ◽  
Evertine J Abbink ◽  
Angela Colbers ◽  
Joost P H Drenth ◽  
...  
Keyword(s):  
Drug Exposure ◽  
Swallowing Disorders ◽  
Similarity Criteria ◽  
Fixed Dose Combination ◽  
Fixed Dose ◽  
Pharmacokinetic Parameters ◽  
Serious Adverse Events ◽  
Combination Tablet ◽  
Significant Difference ◽  
Dose Combination

Abstract Background Finding a suitable treatment for HCV patients with swallowing disorders is still a major challenge. In practice, direct-acting antivirals are crushed without knowledge of adequate absorption. Crushing can alter drug exposure, possibly leading to treatment failure, development of resistance or toxicity. Currently, there is no information about crushing of the fixed-dose combination tablet of elbasvir/grazoprevir; therefore, crushing of this tablet is not recommended. Objectives To investigate the influence of crushing on the pharmacokinetics of the elbasvir/grazoprevir fixed-dose combination tablet. Methods We conducted an open-label, two-period, randomized, cross-over, Phase I, single-dose trial in 11 healthy adult volunteers. Subjects randomly received whole-tablet elbasvir/grazoprevir or crushed and suspended elbasvir/grazoprevir in a fasted state. Pharmacokinetic similarity criteria (90% CIs lie within 70%–143% acceptance range) were used for AUC0–∞ and AUC0–72. Results Mean plasma concentration–time curves of elbasvir and grazoprevir showed similar pharmacokinetic profiles. The primary pharmacokinetic parameters AUC0–∞ and AUC0–72 of elbasvir and grazoprevir after intake of a crushed tablet were on average 12%–16% higher compared with the whole tablet, but 90% CIs were all within the predefined boundaries of pharmacokinetic similarity. Crushing leads to a higher Cmax of grazoprevir (42%); no significant difference was found between treatments with regard to the Cmax of elbasvir. No serious adverse events were reported during the trial. Conclusions Pharmacokinetic similarity could be demonstrated for a crushed and suspended tablet compared with a whole tablet, without impacting drug safety or efficacy. Crushed and suspended administration of elbasvir/grazoprevir can be used in patients with swallowing disorders.

scholarly journals Pharmacokinetic profile of amodiaquine and its active metabolite desethylamodiaquine in Ghanaian patients with uncomplicated falciparum malaria

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Thomas A. Anyorigiya ◽  
Sandra Castel ◽  
Katya Mauff ◽  
Frank Atuguba ◽  
Bernhards Ogutu ◽  
...  
Keyword(s):  
Falciparum Malaria ◽  
Active Metabolite ◽  
Drug Exposure ◽  
Age Groups ◽  
Uncomplicated Falciparum Malaria ◽  
Fixed Dose ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Close Monitoring ◽  
Drug Concentrations

Abstract Background Accurate measurement of anti-malarial drug concentrations in therapeutic efficacy studies is essential to distinguish between inadequate drug exposure and anti-malarial drug resistance, and to inform optimal anti-malarial dosing in key target population groups. Methods A sensitive and selective LC–MS/MS method was developed and validated for the simultaneous determination of amodiaquine and its active metabolite, desethylamodiaquine, and used to describe their pharmacokinetic parameters in Ghanaian patients with uncomplicated falciparum malaria treated with the fixed-dose combination, artesunate-amodiaquine. Results The day-28 genotype-adjusted adequate clinical and parasitological response rate in 308 patients studied was > 97% by both intention-to-treat and per-protocol analysis. After excluding 64 patients with quantifiable amodiaquine concentrations pre-treatment and 17 with too few quantifiable concentrations, the pharmacokinetic analysis included 227 patients (9 infants, 127 aged 1–4 years, 91 aged ≥ 5 years). Increased median day-3 amodiaquine concentrations were associated with a lower risk of treatment failure [HR 0.87 (95% CI 0.78–0.98), p = 0.021]. Amodiaquine exposure (median AUC0-∞) was significantly higher in infants (4201 ng h/mL) and children aged 1–5 years (1994 ng h/mL) compared to older children and adults (875 ng h/mL, p = 0.001), even though infants received a lower mg/kg amodiaquine dose (median 25.3 versus 33.8 mg/kg in older patients). Desethylamodiaquine AUC0-∞ was not significantly associated with age. No significant safety concerns were identified. Conclusions Efficacy of artesunate-amodiaquine at currently recommended dosage regimens was high across all age groups. Reassuringly, amodiaquine and desethylamodiaquine exposure was not reduced in underweight-for-age young children or those with high parasitaemia, two of the most vulnerable target populations. A larger pharmacokinetic study with close monitoring of safety, including full blood counts and liver function tests, is needed to confirm the higher amodiaquine exposure in infants, understand any safety implications and assess whether dose optimization in this vulnerable, understudied population is needed.

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