lumefantrine and HIV-Infections

Treating malaria in HIV-coinfected individuals should consider potential drug-drug interactions. Artemether-lumefantrine is the most widely recommended treatment for uncomplicated malaria globally. Lumefantrine is metabolized by CYP3A4, an enzyme that commonly used antiretrovirals often induce or inhibit. A population pharmacokinetic meta-analysis was conducted using individual participant data from 10 studies with 6,100 lumefantrine concentrations from 793 nonpregnant adult participants (41% HIV-malaria-coinfected, 36% malaria-infected, 20% HIV-infected, and 3% healthy volunteers). Lumefantrine exposure increased 3.4-fold with coadministration of lopinavir-ritonavir-based antiretroviral therapy (ART), while it decreased by 47% with efavirenz-based ART and by 59% in the patients with rifampin-based antituberculosis treatment. Nevirapine- or dolutegravir-based ART and malaria or HIV infection were not associated with significant effects. Monte Carlo simulations showed that those on concomitant efavirenz or rifampin have 49% and 80% probability of day 7 concentrations <200 ng/ml, respectively, a threshold associated with an increased risk of treatment failure. The risk of achieving subtherapeutic concentrations increases with larger body weight. An extended 5-day and 6-day artemether-lumefantrine regimen is predicted to overcome these drug-drug interactions with efavirenz and rifampin, respectively.

Topics: Adolescent; Adult; Aged; Anti-HIV Agents; Antimalarials; Antiretroviral Therapy, Highly Active; Artemether, Lumefantrine Drug Combination; Body Weight; Computer Simulation; Drug Interactions; Female; HIV Infections; Humans; Lopinavir; Lumefantrine; Malaria; Male; Middle Aged; Monte Carlo Method; Ritonavir; Young Adult

When people with human immunodeficiency virus (HIV) infection (PWH) develop malaria, they are at risk of poor anti-malarial treatment efficacy resulting from impairment in the immune response and/or drug-drug interactions that alter anti-malarial metabolism. The therapeutic efficacy of artemether-lumefantrine was evaluated in a cohort of PWH on antiretroviral therapy (ART) and included measurement of day 7 lumefantrine levels in a subset to evaluate for associations between lumefantrine exposure and treatment response.. Adults living with HIV (≥ 18 years), on ART for ≥ 6 months with undetectable HIV RNA viral load and CD4 count ≥ 250/mm. 411 malaria episodes were observed among 186 participants over 5 years. The unadjusted ACPR rate was 81% (95% CI 77-86). However, after PCR correction to exclude new infections, ACPR rate was 94% (95% CI 92-97). Increasing age and living in Ndirande were associated with decreased hazard of treatment failure. In this population of adults with HIV on ART, 54% (51/94) had levels below a previously defined optimal day 7 lumefantrine level of 200 ng/ml. This occurred more commonly among participants who were receiving an efavirenz-based ART compared to other ART regimens (OR 5.09 [95% CI 1.52-7.9]). Participants who experienced treatment failure had lower day 7 median lumefantrine levels (91 ng/ml [95% CI 48-231]) than participants who experienced ACPR (190 ng/ml [95% CI 101-378], p-value < 0.008).. Recurrent malaria infections are frequent in this population of PWH on ART. The PCR-adjusted efficacy of AL meets the WHO criteria for acceptable treatment efficacy. Nevertheless, lumefantrine levels tend to be low in this population, particularly in those on efavirenz-based regimens, with lower concentrations associated with more frequent malaria infections following treatment. These results highlight the importance of understanding drug-drug interactions when diseases commonly co-occur.

Topics: Adult; Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Drug Combinations; Ethanolamines; Fluorenes; HIV Infections; Humans; Lumefantrine; Malaria; Malaria, Falciparum; Malawi; Treatment Outcome

Artemether-lumefantrine is currently the most widely recommended treatment of uncomplicated malaria. Lopinavir-based antiretroviral therapy is the commonly recommended second-line HIV treatment. Artemether and lumefantrine are metabolised by cytochrome P450 isoenzyme CYP3A4, which lopinavir/ritonavir inhibits, potentially causing clinically important drug-drug interactions.. An adaptive, parallel-design safety and pharmacokinetic study was conducted in HIV-infected (malaria-negative) patients: antiretroviral-naïve and those stable on lopinavir/ritonavir-based antiretrovirals. Both groups received the recommended six-dose artemether-lumefantrine treatment. The primary outcome was day-7 lumefantrine concentrations, as these correlate with antimalarial efficacy. Adverse events were solicited throughout the study, recording the onset, duration, severity, and relationship to artemether-lumefantrine.. We enrolled 34 patients. Median day-7 lumefantrine concentrations were almost 10-fold higher in the lopinavir than the antiretroviral-naïve group [3170 versus 336 ng/mL; p = 0.0001], with AUC(0-inf) and Cmax increased five-fold [2478 versus 445 μg.h/mL; p = 0.0001], and three-fold [28.2 versus 8.8 μg/mL; p < 0.0001], respectively. Lumefantrine Cmax, and AUC(0-inf) increased significantly with mg/kg dose in the lopinavir, but not the antiretroviral-naïve group. While artemether exposure was similar between groups, Cmax and AUC(0-8h) of its active metabolite dihydroartemisinin were initially two-fold higher in the lopinavir group [p = 0.004 and p = 0.0013, respectively]. However, this difference was no longer apparent after the last artemether-lumefantrine dose. Within 21 days of starting artemether-lumefantrine there were similar numbers of treatment emergent adverse events (42 vs. 35) and adverse reactions (12 vs. 15, p = 0.21) in the lopinavir and antiretroviral-naïve groups, respectively. There were no serious adverse events and no difference in electrocardiographic QTcF- and PR-intervals, at the predicted lumefantrine Tmax.. Despite substantially higher lumefantrine exposure, intensive monitoring in our relatively small study raised no safety concerns in HIV-infected patients stable on lopinavir-based antiretroviral therapy given the recommended artemether-lumefantrine dosage. Increased day-7 lumefantrine concentrations have been shown previously to reduce the risk of malaria treatment failure, but further evidence in adult patients co-infected with malaria and HIV is needed to assess the artemether-lumefantrine risk : benefit profile in this vulnerable population fully. Our antiretroviral-naïve patients confirmed previous findings that lumefantrine absorption is almost saturated at currently recommended doses, but this dose-limited absorption was overcome in the lopinavir group.. Clinical Trial Registration number NCT00869700. Registered on clinicaltrials.gov 25 March 2009.

Topics: Adult; Anti-HIV Agents; Artemether; Artemisinins; Drug Interactions; Ethanolamines; Female; Fluorenes; HIV Infections; HIV-1; Humans; Lopinavir; Lumefantrine; Male; Ritonavir

Etravirine is a substrate and inducer of cytochrome P450 (CYP) 3A and a substrate and inhibitor of CYP2C9 and CYPC2C19. Darunavir/ritonavir is a substrate and inhibitor of CYP3A. Artemether and lumefantrine are primarily metabolized by CYP3A; artemether is also metabolized to a lesser extent by CYP2B6, CYP2C9 and CYP2C19. Artemether has an active metabolite, dihydroartemisinin. The objective was to investigate pharmacokinetic interactions between darunavir/ritonavir or etravirine and arthemether/lumefrantrine.. This single-centre, randomized, two-way, two-period cross-over study included 33 healthy volunteers. In panel 1, 17 healthy volunteers received two treatments (A and B) in random order, with a washout period of 4 weeks between treatments: treatment A: artemether/lumefantrine 80/480 mg alone, in a 3-day course; treatment B: etravirine 200 mg twice a day (bid) for 21 days with artemether/lumefantrine 80/480 mg from day 8 (a 3-day treatment course). In panel 2, another 16 healthy volunteers received two treatments, similar to those in panel 1 but instead of etravirine, darunavir/ritonavir 600/100 mg bid was given.. Overall, 28 of the 33 volunteers completed the study. Co-administration of etravirine reduced the area under the plasma concentration-time curve (AUC) of artemether [by 38%; 90% confidence interval (CI) 0.48-0.80], dihydroartemisinin (by 15%; 90% CI 0.75-0.97) and lumefantrine (by 13%; 90% CI 0.77-0.98) at steady state. Co-administration of darunavir/ritonavir reduced the AUC of artemether (by 16%; 90% CI 0.69-1.02) and dihydroartemisinin (by 18%; 90% CI 0.74-0.91) but increased lumefantrine (2.75-fold; 90% CI 2.46-3.08) at steady state. Co-administration of artemether/lumefantrine had no effect on etravirine, darunavir or ritonavir AUC. No drug-related serious adverse events were reported during the study.. Co-administration of etravirine with artemether/lumefantrine may lower the antimalarial activity of artemether and should therefore be used with caution. Darunavir/ritonavir can be co-administered with artemether/lumefantrine without dose adjustment but should be used with caution.

Topics: Adult; Anti-HIV Agents; Antimalarials; Artemether; Artemisinins; Cross-Over Studies; Darunavir; Drug Interactions; Ethanolamines; Fluorenes; Healthy Volunteers; HIV; HIV Infections; Humans; Lumefantrine; Malaria; Middle Aged; Nitriles; Pyridazines; Pyrimidines; Ritonavir; Sulfonamides

Human immunodeficiency virus (HIV)-1 infected adults with low CD4 cell count have a higher risk of malaria infection and clinical malaria. We assessed the influence that HIV-1 immune suppression has on the efficacy of antimalarial treatment in adults with uncomplicated malaria.. This clinical trial included 971 Zambian adults with uncomplicated malaria. Patients were tested for HIV-1, and, if positive, a CD4 cell count was assessed. The primary outcome was recurrent parasitemia corrected by molecular genotyping within 45 days after treatment.. HIV-1 infection was detected in 33% (320/971) of adult patients with malaria. Treatment failure was not associated with HIV-1 infection (relative risk [RR], 1.12 [95% confidence interval {CI}, 0.82-1.53]; P=.45). HIV-1-infected patients with a CD4 cell count <300 cells/microL had an increased risk of recurrent parasitemia, compared with those with a CD4 cell count >or=300 cells/microL (RR, 2.24 [95% CI, 1.20-4.14]; P=.01). After genotyping, the risk of recrudescence was higher in HIV-1-infected patients with a CD4 cell count <300 cells/microL than in the other patients with malaria (RR, 1.67 [95% CI, 1.13-2.47]; P=.02).. HIV-1-infected patients with malaria with a CD4 cell count <300 cells/microL have a higher risk of experiencing a recrudescent infection, compared with those with a CD4 cell count >or=300 cells/microL or without HIV-1 infection. Trial registered at http://www.clinicaltrials.gov/; reference number NCT00304980.

Topics: Adolescent; Adult; Animals; Antimalarials; Artemether; Artemisinins; CD4 Lymphocyte Count; Drug Combinations; Ethanolamines; Female; Fluorenes; HIV Infections; HIV-1; Humans; Immunosuppression Therapy; Lumefantrine; Malaria, Falciparum; Male; Middle Aged; Pyrimethamine; Sulfadoxine; Treatment Failure; Treatment Outcome; Zambia

Artemisinin-based combination therapies (ACTs) are the primary treatment for malaria. It is essential to characterize the pharmacokinetics (PKs) and pharmacodynamics (PDs) of ACTs in vulnerable populations at risk of suboptimal dosing. We developed a population PK/PD model using data from our previous study of artemether-lumefantrine in HIV-uninfected and HIV-infected children living in a high-transmission region of Uganda. HIV-infected children were on efavirenz-, nevirapine-, or lopinavir-ritonavir-based antiretroviral regimens, with daily trimethoprim-sulfamethoxazole prophylaxis. We assessed selection for resistance in two key parasite transporters, pfcrt and pfmdr1, over 42-day follow-up and incorporated genotyping into a time-to-event model to ascertain how resistance genotype in relation to drug exposure impacts recurrence risk. Two hundred seventy-seven children contributed 364 episodes to the model (186 HIV-uninfected and 178 HIV-infected), with recurrent microscopy-detectable parasitemia detected in 176 episodes by day 42. The final model was a two-compartment model with first-order absorption and an estimated age effect on bioavailability. Systemic lumefantrine exposure was highest with lopinavir-ritonavir, lowest with efavirenz, and equivalent with nevirapine and HIV-uninfected children. HIV status and lumefantrine concentration were significant factors associated with recurrence risk. Significant selection was demonstrated for pfmdr1 N86 and pfcrt K76 in recurrent infections, with no evidence of selection for pfmdr1 Y184F. Less sensitive parasites were able to tolerate lumefantrine concentrations ~ 3.5-fold higher than more sensitive parasites. This is the first population PK model of lumefantrine in HIV-infected children and demonstrates selection for reduced lumefantrine susceptibility, a concern as we confront the threat to ACTs posed by emerging artemisinin resistance in Africa.

Topics: Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Drug Combinations; Fluorenes; HIV Infections; Humans; Lopinavir; Lumefantrine; Malaria; Malaria, Falciparum; Nevirapine; Ritonavir; Uganda

The choice of malaria treatment for HIV-infected pregnant women receiving efavirenz-based antiretroviral therapy must consider the potential impact of drug interactions on antimalarial exposure and clinical response. The aim of this study was to investigate the effects of efavirenz on artemether-lumefantrine (AL) because no studies have isolated the impact of efavirenz for HIV-infected pregnant women.. A prospective clinical pharmacokinetic (PK) study compared HIV-infected, efavirenz-treated pregnant women with HIV-uninfected pregnant women in Tororo, Uganda. All women received the standard 6-dose AL treatment regimen for Plasmodium falciparum malaria with intensive PK samples collected over 21 days and 42-days of clinical follow-up. PK exposure parameters were calculated for artemether, its active metabolite dihydroartemisinin (DHA), and lumefantrine to determine the impact of efavirenz.. Nine HIV-infected and 30 HIV-uninfected pregnant women completed intensive PK evaluations. Relative to controls, concomitant efavirenz therapy lowered the 8-hour artemether concentration by 76% (P = 0.013), DHA peak concentration by 46% (P = 0.033), and day 7 and 14 lumefantrine concentration by 61% and 81% (P = 0.046 and 0.023), respectively. In addition, there were nonsignificant reductions in DHA area under the concentration-time curve0-8hr (35%, P = 0.057) and lumefantrine area under the concentration-time curve0-∞ (34%, P = 0.063) with efavirenz therapy.. Pregnant HIV-infected women receiving efavirenz-based antiretroviral therapy during malaria treatment with AL showed reduced exposure to both the artemisinin and lumefantrine. These data suggest that malaria and HIV coinfected pregnant women may require adjustments in AL dosage or treatment duration to achieve exposure comparable with HIV-uninfected pregnant women.

Topics: Adolescent; Adult; Alkynes; Anti-HIV Agents; Anti-Retroviral Agents; Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Benzoxazines; Cyclopropanes; Drug Combinations; Drug Interactions; Female; HIV Infections; Humans; Lumefantrine; Malaria; Malaria, Falciparum; Pregnancy; Prospective Studies; Uganda; Young Adult

Lumefantrine is a long-acting antimalarial drug with an elimination half-life of over 3 days and protein binding of 99 percent. Correlation of lumefantrine concentrations from capillary plasma via fingerprick (Cc) versus venous plasma (Cv) remains to be defined.. Venous and capillary plasma samples were collected simultaneously from children, pregnant women, and non-pregnant adults at 2, 24, 120hr post last dose of a standard 3-day artemether-lumefantrine regimen they received for uncomplicated malaria. Some of the enrolled children and pregnant women were also HIV-infected. Samples were analyzed via liquid chromatography tandem mass spectrometry. Linear regression analysis was performed using the program Stata® SE12.1.. In children, the linear regression equations for Cc vs Cv at 2, 24, and 120hr (day 7) post dose are [Cc] = 1.05*[Cv]+95.0 (n = 142, R2 = 0.977), [Cc] = 0.995*[Cv]+56.7 (n = 147, R2 = 0.990) and [Cc] = 0.958*[Cv]+18.6 (n = 139, R2 = 0.994), respectively. For pregnant women, the equations are [Cc] = 1.04*[Cv]+68.1 (n = 43, R2 = 0.990), [Cc] = 0.997*[Cv]+37.3 (n = 43, R2 = 0.993) and [Cc] = 0.941*[Cv]+11.1 (n = 41, R2 = 0.941), respectively. For non-pregnant adults, the equations are [Cc] = 1.05*[Cv]-117 (n = 32, R2 = 0.958), [Cc] = 0.962*[Cv]+9.21 (n = 32, R2 = 0.964) and [Cc] = 1.04*[Cv]-40.1 (n = 32, R2 = 0.988), respectively. In summary, a linear relationship with a slope of ~1 was found for capillary and venous lumefantrine levels in children, pregnant women and non-pregnant adults at 2hr, 24hr and 120hr post last dose, representing absorption, distribution, and elimination phases.. Capillary and venous plasma concentration of lumefantrine can be used interchangeably at 1:1 ratio. Capillary sampling method via finger prick is a suitable alternative for sample collection in clinical studies.

Topics: Antimalarials; Child; Chromatography, Liquid; Coinfection; Drug Monitoring; Female; HIV Infections; Humans; Lumefantrine; Malaria; Pregnancy; Tandem Mass Spectrometry; Time Factors

As more and more generics become available in the market place, the safety/efficacy concerns may arise as the result of interchangeably use of approved generics. However, bioequivalence assessment for regulatory approval among generics of the innovative drug product is not required. In practice, approved generics are often used interchangeably without any mechanism of safety monitoring. In this article, based on indirect comparisons, we proposed several methods to assessing bioequivalence and interchangeability between generics. The applicability of the methods and the similarity assumptions were discussed, as well as the inappropriateness of directly adopting adjusted indirect comparison to the field of generics' comparison. Besides, some extensions were given to take into consideration the important topics in clinical trials for bioequivalence assessments, for example, multiple comparisons and simultaneously testing bioequivalence among three generics. Extensive simulation studies were conducted to investigate the performances of the proposed methods. The studies of malaria generics and HIV/AIDS generics prequalified by the WHO were used as real examples to demonstrate the use of the methods. Copyright © 2017 John Wiley & Sons, Ltd.

Topics: Anti-HIV Agents; Antimalarials; Artemether; Artemisinins; Computer Simulation; Confidence Intervals; Drugs, Generic; Ethanolamines; Fluorenes; HIV Infections; Humans; Lamivudine; Lumefantrine; Malaria; Models, Statistical; Therapeutic Equivalency; Zidovudine

In our country, within years, despite a dramatic drop in the number of patients with malaria, a dramatic increase in the number of patients with import malaria is noteworthy. A 32-year-old male patient presented with fever, shivering, malaise, and loss of appetite. He had travelled to West Africa. Laboratory findings were as follows: hemoglobin: 8.8 g/dL and anti-HIV: positive. Microscopic examinations of thin blood smears and thick blood preparations revealed widespread trophozoites. The presence of double-dotted ring forms and banana-shaped gametocytes resulted in Plasmodium falciparum malaria being diagnosed. The patient was started treatment with oral artemether 20 mg/ lumefantrine 120 mg 2×4 tablets and trimethoprim-sulfamethoxazole. During his follow-up, hemoglobin levels regressed to 5.8 g/dL. The patient was diagnosed as having severe malaria. He visited our hematology unit, and exchange transfusion (EET) was recommended. Using an EET apheresis device, eight units of erythrocyte suspension was transfused. The cured patient was discharged. This case was found to be interesting and reminds us the possible presence of comorbid conditions associated with malaria in patients who have a history of travelling abroad. Although its effectiveness has not been proved thus far, as a striking result, EET was used as an alternative treatment in a patient with severe malaria.

Topics: Adult; Africa South of the Sahara; Antimalarials; Artemether; Artemisinins; Coinfection; Diagnosis, Differential; Erythrocyte Transfusion; Ethanolamines; Fluorenes; HIV Infections; Humans; Lumefantrine; Malaria, Falciparum; Male; Plasmodium falciparum; Severity of Illness Index; Travel; Turkey

We investigated the influence of efavirenz (EFV)- or nevirapine (NVP)-based antiretroviral therapy (ART) on lumefantrine plasma exposure in HIV-malaria-coinfected patients and implication of pharmacogenetic variations. A total of 269 HIV patients with uncomplicated falciparum malaria on NVP-based ART (NVP-arm), EFV-based ART (EFV-arm) or not receiving ART (control-arm) were enrolled and treated with artemether-lumefantrine. Day-7 lumefantrine, baseline EFV and NVP plasma concentrations, and CYP2B6*6,*18, CYP3A4*1B, CYP3A5*3,*6,*7, ABCB1 c.3435C>T and ABCB1 c.4036A>G genotypes were determined. The median day-7 lumefantrine plasma concentration was significantly lower in the EFV-arm compared with that in NVP- and control-arm. High EFV plasma concentrations and CYP2B6*6/*6 genotype significantly correlated with low lumefantrine plasma concentrations and high rate of recurrent parasitemia. No significant effect of NVP-based ART on lumefantrine exposure was observed. In conclusion, owing to long-term CYP3A induction, EFV-based ART cotreatment significantly reduces lumefantrine plasma exposure leading to poor malaria treatment response, which is more pronounced in CYP2B6 slow metabolizers.

Topics: Alkynes; Anti-HIV Agents; Antimalarials; Artemether; Artemisinins; ATP Binding Cassette Transporter, Subfamily B; Benzoxazines; Case-Control Studies; Coinfection; Cyclopropanes; Cytochrome P-450 CYP2B6; Cytochrome P-450 CYP3A; Drug Antagonism; Drug Therapy, Combination; Ethanolamines; Fluorenes; Genotype; HIV Infections; Humans; Lumefantrine; Malaria; Nevirapine; Prospective Studies

HIV-malaria co-infected patients in most parts of sub-Saharan Africa are treated with both artemether-lumefantrine (AL) and efavirenz (EFV) or nevirapine (NVP)-based antiretroviral therapy (ART). EFV, NVP, artemether and lumefantrine are substrates, inhibitors or inducers of CYP3A4 and CYP2B6, creating a potential for drug-drug interactions. The effect of EFV and/or NVP on lumefantrine pharmacokinetic profile among HIV-malaria co-infected patients on ART and treated with AL was investigated. Optimal lumefantrine dosage regimen for patients on EFV-based ART was determined by population pharmacokinetics and simulation.. This was a non-randomized, open label, parallel, prospective cohort study in which 128, 66 and 75 HIV-malaria co-infected patients on NVP-based ART (NVP-arm), EFV-based ART (EFV-arm) and ART naïve (control-am) were enrolled, respectively. Patients were treated with AL and contributed sparse venous plasma samples. Pharmacokinetic analysis of lumefantrine was done using non-linear mixed effect modelling.. Of the evaluated models, a two-compartment pharmacokinetic model with first order absorption and lag-time described well lumefantrine plasma concentrations time profile. Patients in the EFV-arm but not in the NVP-arm had significantly lower lumefantrine bioavailability compared to that in the control-arm. Equally, 32% of patients in the EFV-arm had day-7 lumefantrine plasma concentrations below 280 ng/ml compared to only 4% in the control-arm and 3% in the NVP-arm. Upon post hoc simulation of lumefantrine exposure, patients in the EFV-arm had lower exposure (median (IQR)) compared to that in the control-arm; AUC0-inf; was 303,130 (211,080-431,962) versus 784,830 (547,405-1,116,250); day-7 lumefantrine plasma concentrations was: 335.5 (215.8-519.5) versus 858.7 (562.3-1,333.8), respectively. The predictive model through simulation of lumefantrine exposure at different dosage regimen scenarios for patients on EFV-based ART, suggest that AL taken twice daily for five days using the current dose could improve lumefantrine exposure and consequently malaria treatment outcomes.. Co-treatment of AL with EFV-based ART but not NVP-based ART significantly reduces lumefantrine bioavailability and consequently total exposure. To ensure adequate lumefantrine exposure and malaria treatment success in HIV-malaria co-infected patients on EFV-based ART, an extension of the duration of AL treatment to five days using the current dose is proposed.

Topics: Adult; Aged; Alkynes; Anti-Retroviral Agents; Antimalarials; Benzoxazines; Cyclopropanes; Drug Interactions; Ethanolamines; Female; Fluorenes; HIV Infections; Humans; Lumefantrine; Malaria; Male; Middle Aged; Nevirapine; Prospective Studies; Tanzania; Young Adult

Coadministration of nevirapine-based antiretroviral therapy (ART) and artemether-lumefantrine is reported to result in variable changes in lumefantrine exposure. We conducted an intensive pharmacokinetic study with 11 HIV-infected adults who were receiving artemether-lumefantrine plus nevirapine-based ART, and we compared the results with those for 16 HIV-negative adult historical controls. Exposure to artemether and lumefantrine was significantly lower and dihydroartemisinin exposure was unchanged in subjects receiving nevirapine-based ART, compared with controls. Nevirapine exposure was unchanged before and after artemether-lumefantrine administration.

Topics: Adult; Anti-HIV Agents; Antimalarials; Artemether; Artemisinins; Case-Control Studies; Coinfection; Drug Combinations; Drug Interactions; Ethanolamines; Female; Fluorenes; HIV Infections; HIV-1; Humans; Lumefantrine; Malaria, Falciparum; Male; Nevirapine; Nigeria; Plasmodium falciparum

To investigate the pharmacokinetics of artemether, dihydroartemisinin and lumefantrine during rifampicin intake and after stopping rifampicin.. An open-label, two-phase, longitudinal drug interaction study with patients serving as their own controls.. We recruited HIV-1-seropositive Ugandan adults who were receiving rifampicin-based tuberculosis treatment and who did not have malaria. Pharmacokinetic sampling after six doses of artemether-lumefantrine was performed during rifampicin-based tuberculosis treatment (phase 1) and repeated at least 3 weeks after stopping rifampicin-based tuberculosis treatment (phase 2).. Six and five patients completed phases 1 and 2, respectively. Median age and weight were 30 years and 64 kg. Artemether and dihydroartemisinin area under the concentration-time curve (AUC(0-12h)) were significantly lower by 89% [geometric mean ratio (GMR) 90% confidence interval (CI) 0.11, 0.05-0.26] and 85% (0.15, 0.10-0.23), respectively, during rifampicin-based treatment when compared to AUC(0-12h) after stopping rifampicin intake. Similarly, artemether and dihydroartemisinin C(max) were 83% (0.17, 0.08-0.39) and 78% (0.22, 0.15-0.33) lower, respectively, during rifampicin treatment. For artemether, mean (±SD) C(12) was 0.5(±1.0) and 5.9(±2.5) ng/ml in phases 1 and 2, respectively. Corresponding values for dihydroartemisinin (DHA) were 0.3(±0.4) and 4.7(±2.0) ng/ml, respectively. Day 8 lumefantrine concentration was significantly lower by 84% (GMR 90% CI 0.16, 0.09-0.27), and AUC(Day3-Day25) was significantly lower by 68% (GMR 90% CI 0.32, 0.21-0.49) during rifampicin-based treatment when compared to exposure values after stopping rifampicin.. Pharmacokinetic parameters for artemether-lumefantrine were markedly lower during rifampicin-based tuberculosis treatment. Artemether-lumefantrine should not be co-administered with rifampicin.

Topics: Adult; Antimalarials; Antitubercular Agents; Artemether; Artemisinins; Drug Antagonism; Ethanolamines; Female; Fluorenes; HIV Infections; Humans; Longitudinal Studies; Lumefantrine; Male; Rifampin; Tuberculosis; Uganda

Topics: Adult; Antimalarials; Artemether; Artemisinins; Drug Combinations; Ethanolamines; Fluorenes; HIV Infections; Humans; Lumefantrine; Malaria, Falciparum; Male; Plasmodium malariae; Treatment Failure