Efavirenz-Based Antiretroviral Therapy Reduces Artemether–Lumefantrine Exposure for Malaria Treatment in HIV-Infected Pregnant Women

Hughes, Emma; Mwebaza, Norah; Huang, Liusheng; Kajubi, Richard; Nguyen, Vy; Nyunt, Myaing M.; Orukan, Francis; Mwima, Moses W; Parikh, Sunil; Aweeka, Francesca

doi:10.1097/qai.0000000000002237

Cited by 10 publications

(11 citation statements)

References 38 publications

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“…Clinical trial simulations based on the final PK/PD models found that extending treatment to 5 or 7 days would equalize lumefantrine exposure between those receiving an interacting ART regimen, and those who do not take these drugs. Although the studies discussed above enrolled adult patients, similar results have been seen in children and pregnant women indicating the universal benefit of dosing changes for all patient populations 50‐56 . In addition to testing these novel regimens, the importance of designing the next set of clinical trials to collect and integrate treatment outcome data should not be overlooked.…”

Section: Act Drug‐drug Interactionsmentioning

confidence: 85%

“…Although the studies discussed above enrolled adult patients, similar results have been seen in children and pregnant women indicating the universal benefit of dosing changes for all patient populations. 50 , 51 , 52 , 53 , 54 , 55 , 56 In addition to testing these novel regimens, the importance of designing the next set of clinical trials to collect and integrate treatment outcome data should not be overlooked. Along with understanding how DDIs impact antimalarial PK exposure, it is equally important to understand their effects on parasite clearance rates and treatment outcomes.…”

Section: Act Drug‐drug Interactionsmentioning

confidence: 99%

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Malaria PK/PD and the Role Pharmacometrics Can Play in the Global Health Arena: Malaria Treatment Regimens for Vulnerable Populations

Hughes

Wallender

Ali

et al. 2021

Clin Pharma and Therapeutics

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Malaria is an infectious disease which disproportionately effects children and pregnant women. These vulnerable populations are often excluded from clinical trials resulting in one‐size‐fits‐all treatment regimens based on those established for a nonpregnant adult population. Pharmacokinetic/pharmacodynamic (PK/PD) models can be used to optimize dose selection as they define the drug exposure‐response relationship. Additionally, these models are able to identify patient characteristics that cause alterations in the expected PK/PD profiles and through simulations can recommend changes to dosing which compensate for the differences. In this review, we examine how PK/PD models have been applied to optimize antimalarial dosing recommendations for young children, including those who are malnourished, pregnant women, and individuals receiving concomitant therapies such as those for HIV treatment. The malaria field has had great success in utilizing PK/PD models as a foundation to update treatment guidelines and propose the next generation of dosing regimens to investigate in clinical trials. We propose how the malaria field can continue to use modeling to improve therapies by further integrating PK data into clinical studies and including data on drug resistance and host immunity in PK/PD models. Finally, we suggest that other disease areas can achieve similar success in applying pharmacometrics to improve outcomes by implementing three key principals.

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Section: Act Drug‐drug Interactionsmentioning

confidence: 85%

Section: Act Drug‐drug Interactionsmentioning

confidence: 99%

Malaria PK/PD and the Role Pharmacometrics Can Play in the Global Health Arena: Malaria Treatment Regimens for Vulnerable Populations

Hughes

Wallender

Ali

et al. 2021

Clin Pharma and Therapeutics

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Section: Discussionmentioning

confidence: 98%

“…7 The findings among children in Uganda and Malawi were likely a result of the pharmacokinetic interaction between LPV/r and lumefantrine rather than between efavirenz and artemether. 20 In adults, no difference in malaria incidence was observed in women receiving a PI-based vs. nNRTI-based ART. 8 We did not find a statistically significant difference in parasite clearance rates nor in time-to-parasite clearance between PI and nNRTI treatment arms.…”

Section: Discussionmentioning

confidence: 98%

Brief Report: No Differences Between Lopinavir/Ritonavir and Nonnucleoside Reverse Transcriptase Inhibitor–Based Antiretroviral Therapy on Clearance of Plasmodium falciparum Subclinical Parasitemia in Adults Living With HIV Starting Treatment (A5297)

Shaffer¹,

Kumwenda

Chen

et al. 2022

JAIDS Journal of Acquired Immune Deficiency Syndromes

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Background:HIV protease inhibitors anti-Plasmodium falciparum activity in adults remains uncertain.Methods:Adults with HIV CD4+ counts >200 cells/mm3 starting antiretroviral therapy (ART) with P. falciparum subclinical parasitemia (Pf SCP) were randomized 1:1 to (step 1) protease inhibitor lopinavir/ritonavir (LPV/r)-based (arm A) or nonnucleoside reverse transcriptase inhibitor (nNRTI)-based ART (arm B) for 15 days. In step 2, participants received nNRTI-based ART and trimethoprim/sulfamethoxazole prophylaxis for 15 days. P. falciparum SCP clearance was measured by polymerase chain reaction. The Fisher exact test [95% exact confidence interval (CI)] was used to compare proportions of P. falciparum SCP clearance (<10 parasites/μL on 3 occasions within 24 hours) between LPV/r and nNRTI arms at day 15. The Kaplan–Meier method and log-rank test were used to compare time-to-clearance.Results:Fifty-two adults from Kenya, Malawi, and Uganda with a median age = 31 (Q1, Q3: 24–39) years, 33% women, with baseline median CD4+ counts of 324 (259–404) cells/mm3, median HIV-1 RNA viremia of 5.18 log10 copies/mL (4.60–5.71), and median estimated P. falciparum density of 454 parasites/μL (83–2219) enrolled in the study. Forty-nine (94%) participants completed the study. At day 15, there was no statistically significant difference in the proportions of P. falciparum SCP clearance between the LPV/r (23.1% clearance; 6 of the 26) and nNRTI (26.9% clearance; 7 of the 26) arms [between-arm difference 3.9% (95% CI, −21.1% to 28.4%; P = 1.00)]. No significant difference in time-to-clearance was observed between the arms (P = 0.80).Conclusions:In a small randomized study of adults starting ART with P. falciparum SCP, no statistically significant differences were seen between LPV/r- and nNRTI-based ART in P. falciparum SCP clearance after 15 days of treatment.

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“…AUC and C max ratios (German et al, 2009). Contrastingly, other studies found that co-treatment of artemether-lumefantrine with efavirenz significantly decreased artemisinin and lumefantrine bioavailability and total exposure (E. Hughes et al, 2020), highlighting that different anti-retroviral influence anti-malarial drug metabolism differently.…”

Section: Co-morbidities and Combination Of Antimalarial Drugs With Ot...mentioning

confidence: 88%

Anti‐malarial drugs: Mechanisms underlying their proarrhythmic effects

Saadeh

Kumar

Fazmin

et al. 2022

British J Pharmacology

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Malaria remains the leading cause of parasitic death in the world. Artemisinin resistance is an emerging threat indicating an imminent need for novel combination therapy. Given the key role of mass drug administration, it is pivotal that the safety of anti-malarial drugs is investigated thoroughly prior to widespread use. Cardiotoxicity, most prominently arrhythmic risk, has been a concern for anti-malarial drugs. We clarify the likely underlying mechanisms by which anti-malarial drugs predispose to arrhythmias. These relate to disruption of (1) action potential upstroke due to effects on the sodium currents, (2) action potential repolarisation due to effects on the potassium currents, (3) cellular calcium homeostasis, (4) mitochondrial function and reactive oxygen species production and (5) cardiac fibrosis. Together, these alterations promote arrhythmic triggers and substrates. Understanding these mechanisms is essential to assess the safety of these drugs, stratify patients based on arrhythmic risk and guide future anti-malarial drug development.

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Efavirenz-Based Antiretroviral Therapy Reduces Artemether–Lumefantrine Exposure for Malaria Treatment in HIV-Infected Pregnant Women

Cited by 10 publications

References 38 publications

Malaria PK/PD and the Role Pharmacometrics Can Play in the Global Health Arena: Malaria Treatment Regimens for Vulnerable Populations

Malaria PK/PD and the Role Pharmacometrics Can Play in the Global Health Arena: Malaria Treatment Regimens for Vulnerable Populations

Brief Report: No Differences Between Lopinavir/Ritonavir and Nonnucleoside Reverse Transcriptase Inhibitor–Based Antiretroviral Therapy on Clearance of Plasmodium falciparum Subclinical Parasitemia in Adults Living With HIV Starting Treatment (A5297)

Anti‐malarial drugs: Mechanisms underlying their proarrhythmic effects

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