Safety and efficacy of pyronaridine-artesunate paediatric granules in the treatment of uncomplicated malaria in children: insights from randomized clinical trials and a real-world study.

BACKGROUND: Children are particularly at risk of malaria. This analysis consolidates the clinical data for pyronaridine-artesunate (PA) paediatric granules in children from three randomized clinical trials and a real-world study (CANTAM). METHODS: An integrated safety analysis of individual patient data from three randomized clinical trials included patients with microscopically-confirmed Plasmodium falciparum, body weight ≥ 5 kg to < 20 kg, who received at least one dose of study drug (paediatric safety population). PA was administered once daily for 3 days; two trials included the comparator artemether-lumefantrine (AL). PCR-adjusted day 28 adequate clinical and parasitological response (ACPR) was evaluated. Real-world PA granules safety and effectiveness was also considered. RESULTS: In the integrated safety analysis, 63.9% (95% CI 60.2, 67.4; 426/667) of patients had adverse events following PA and 62.0% (95% CI 56.9, 66.9; 222/358) with AL. Vomiting was more common with PA (7.8% [95% CI 6.0, 10.1; 52/667]) than AL (3.4% [95% CI 1.9, 5.8; 12/358]), relative risk 2.3 (95% CI 1.3, 4.3; P = 0.004), occurring mainly following the first PA dose (6.7%, 45/667), without affecting re-dosing or adherence. Prolonged QT interval occurred less frequently with PA (3.1% [95% CI 2.1, 4.8; 21/667]) than AL (8.1% [95% CI 5.7, 11.4; 29/358]), relative risk 0.39 (95% CI 0.22, 0.67; P = 0.0007). In CANTAM, adverse events were reported for 17.7% (95% CI 16.3, 19.2; 460/2599) of patients, most commonly vomiting (5.4% [95% CI 4.6, 6.4; 141/2599]), mainly following the first dose, (4.5% [117/2599]), with all patients successfully re-dosed, and pyrexia (5.4% [95% CI 4.6, 6.3; 140/2599]). In the two comparative clinical trials, Day 28 ACPR in the per-protocol population for PA was 97.1% (95% CI 94.6, 98.6; 329/339) and 100% (95% CI 99.3, 100; 514/514) versus 98.8% (95% CI 95.7, 99.9; 165/167) and 98.4% (95% CI 95.5, 99.7; 188/191) for AL, respectively. In CANTAM, PA clinical effectiveness was 98.0% (95% CI 97.3, 98.5; 2273/2320). CONCLUSIONS: Anti-malarial treatment with PA paediatric granules administered once daily for 3 days was well tolerated in children and displayed good clinical efficacy in clinical trials, with effectiveness confirmed in a real-world study. Trial registration Clinicaltrials.gov: SP-C-003-05: identifier NCT00331136; SP-C-007-07: identifier NCT0541385; SP-C-021-15: identifier NCT03201770. Pan African Clinical Trials Registry: SP-C-013-11: identifier PACTR201105000286876.

Efficacy, Safety, and Pharmacokinetics of Coadministered Diethylcarbamazine, Albendazole, and Ivermectin for Treatment of Bancroftian Filariasis.

BACKGROUND: Available treatments for lymphatic filariasis (LF) are limited in their longterm clearance of microfilaria from the blood. The safety and efficacy of a single-dose triple-drug therapy of the antifilarial drugs diethylcarbamazine (DEC), ivermectin (IVM), and albendazole (ALB) for LF are unknown. METHODS: We performed a pilot study to test the efficacy, safety, and pharmacokinetics of single-dose DEC, IVM, and ALB in Wuchereria bancrofti-infected Papua New Guineans. Adults were randomized into 2 treatment arms, DEC 6 mg/kg + ALB 400 mg (N = 12) or DEC 6 mg/kg + ALB 400 mg + IVM 200 µg/kg (N = 12), and monitored for microfilaria, parasite antigenemia, adverse events (AEs), and serum drug levels. RESULTS: Triple-drug therapy induced >2-log reductions in microfilaria levels at 36 and 168 hours after treatment compared with approximately 1-log reduction with 2 drugs. All 12 individuals who received 3 drugs were microfilaria negative 1 year after treatment, whereas 11 of 12 individuals in the 2-drug regimen were microfilaria positive. In 6 participants followed 2 years after treatment, those who received 3 drugs remained microfilaria negative. AEs, particularly fever, myalgias, pruritus, and proteinuria/hematuria, occurred in 83% vs 50% of those receiving triple-drug compared to 2-drug treatment respectively (P = .021); all resolved within 7 days after treatment. No serious AEs were observed in either group. There was no significant effect of IVM on DEC or ALB drug levels. CONCLUSIONS: Triple-drug therapy is safe and more effective than DEC + ALB for Bancroftian filariasis and has the potential to accelerate elimination of lymphatic filariasis. CLINICAL TRIALS REGISTRATION: NCT01975441.

Efficacy and safety of the mosquitocidal drug ivermectin to prevent malaria transmission after treatment: a double-blind, randomized, clinical trial.

BACKGROUND: Artemisinin combination therapy effectively clears asexual malaria parasites and immature gametocytes but does not prevent posttreatment malaria transmission. Ivermectin (IVM) may reduce malaria transmission by killing mosquitoes that take blood meals from IVM-treated humans. METHODS: In this double-blind, placebo-controlled trial, 120 asymptomatic Plasmodium falciparum parasite carriers were randomized to receive artemether-lumefantrine (AL) plus placebo or AL plus a single or repeated dose (200 µg/kg) of ivermectin (AL-IVM1 and AL-IVM2, respectively). Mosquito membrane feeding was performed 1, 3, and 7 days after initiation of treatment to determine Anopheles gambiae and Anopheles funestus survival and infection rates. RESULTS: The AL-IVM combination was well tolerated. IVM resulted in a 4- to 7-fold increased mortality in mosquitoes feeding 1 day after IVM (P < .001). Day 7 IVM plasma levels were positively associated with body mass index (r = 0.57, P < .001) and were higher in female participants (P = .003), for whom An. gambiae mosquito mortality was increased until 7 days after a single dose of IVM (hazard rate ratio, 1.34 [95% confidence interval, 1.07-1.69]; P = .012). Although we found no evidence that IVM reduced Plasmodium infection rates among surviving mosquitoes, the mosquitocidal effect of AL-IVM1 and AL-IVM2 resulted in 27% and 35% reductions, respectively, in estimated malaria transmission potential during the first week after initiation of treatment. CONCLUSIONS: We conclude that IVM can be safely given in combination with AL and can reduce the likelihood of malaria transmission by reducing the life span of feeding mosquitoes. CLINICAL TRIALS REGISTRATION: NCT0160325.

Population Pharmacokinetics of Pyronaridine in Pediatric Malaria Patients.

Pyramax is a pyronaridine (PYR)-artesunate (PA) combination for the treatment of uncomplicated malaria in adult and pediatric patients. A granule formulation of this combination is being developed for treatment of uncomplicated P. falciparum and P. vivax malaria in pediatric patients. The aims of this study were to describe the pharmacokinetics of PYR using a total of 1,085 blood PYR concentrations available from 349 malaria patients younger than 16 years of age with mild to moderate uncomplicated malaria and to confirm the dosing regimen for the pediatric granule formulation. Nonlinear mixed-effects modeling using NONMEM software was used to obtain the pharmacokinetic and inter- and intraindividual variability parameter estimates. The population pharmacokinetics of PYR were described by a two-compartment model with first-order absorption and elimination. Allometric scaling was implemented to address the effect of body weight on clearance and volume parameters. The final parameter estimates of PYR apparent clearance (CL/F), central volume of distribution (V2/F), peripheral volume of distribution (V3/F), intercompartmental clearance (Q/F), and absorption rate constant (Ka) were 377 liters/day, 2,230 liters, 3,230 liters, 804 liters/day and 17.9 day(-1), respectively. Covariate model building conducted using forward addition (P < 0.05) followed by backward elimination (P < 0.001) yielded two significant covariate-parameter relationships, i.e., age on V2/F and formulation on Ka. Evaluation of bootstrapping, visual predictive check, and condition number indicated that the final model displayed satisfactory robustness, predictive power, and stability. Simulations of PYR concentration-time profiles generated from the final model show similar exposures across pediatric weight ranges, supporting the proposed labeling for weight-based dosing of Pyramax granules. (These studies have been registered at ClinicalTrials.gov under registration no. NCT00331136 [phase II study] and NCT00541385, NCT00403260, NCT00422084, and NCT00440999 [phase III studies]. The most recent phase III study was registered at pactr.org under registration no. PACTR201105000286876.).

Pyronaridine-artesunate versus mefloquine plus artesunate for malaria.

BACKGROUND: Pyronaridine-artesunate is an artemisinin-based combination therapy under evaluation for the treatment of Plasmodium falciparum and P. vivax malaria. METHODS: We conducted a phase 3, open-label, multicenter, noninferiority trial that included 1271 patients between 3 and 60 years of age from Asia (81.3%) or Africa (18.7%) with microscopically confirmed, uncomplicated P. falciparum malaria. Patients underwent randomization for treatment with a fixed-dose combination of 180 mg of pyronaridine and 60 mg of artesunate or with 250 mg of mefloquine plus 100 mg of artesunate. Doses were calculated according to body weight and administered once daily for 3 days. RESULTS: Pyronaridine-artesunate was noninferior to mefloquine plus artesunate for the primary outcome: adequate clinical and parasitologic response in the per-protocol population on day 28, corrected for reinfection with the use of polymerase-chain-reaction (PCR) genotyping. For this outcome, efficacy in the group receiving pyronaridine-artesunate was 99.2% (743 of 749 patients; 95% confidence interval [CI], 98.3 to 99.7) and that in the group receiving mefloquine plus artesunate was 97.8% (360 of 368 patients; 95% CI, 95.8 to 99.1), with a treatment difference of 1.4 percentage points (95% CI, 0.0 to 3.5; P=0.05). In the intention-to-treat population, efficacy on day 42 in the group receiving pyronaridine-artesunate was 83.1% (705 of 848 patients; 95% CI, 80.4 to 85.6) and that in the group receiving mefloquine plus artesunate was 83.9% (355 of 423 patients; 95% CI, 80.1 to 87.3). In Cambodia, where there were 211 study patients, the median parasite clearance time was prolonged for both treatments: 64 hours versus 16.0 to 38.9 hours in other countries (P<0.001, on the basis of Kaplan-Meier estimates). Kaplan-Meier estimates of the recrudescence rate in the intention-to-treat population in Cambodia until day 42 were higher with pyronaridine-artesunate than with mefloquine plus artesunate (10.2% [95% CI, 5.4 to 18.6] vs. 0%; P=0.04 as calculated with the log-rank test), but similar for the other countries combined (4.7% [95% CI, 3.3 to 6.7] and 2.8% [95% CI, 1.5 to 5.3], respectively; P=0.24). Elevated levels of aminotransferases were observed in those receiving pyronaridine-artesunate. Two patients receiving mefloquine plus artesunate had seizures. CONCLUSIONS: Fixed-dose pyronaridine-artesunate was efficacious in the treatment of uncomplicated P. falciparum malaria. In Cambodia, extended parasite clearance times were suggestive of in vivo resistance to artemisinin. (Funded by Shin Poong Pharmaceutical Company and the Medicines for Malaria Venture; ClinicalTrials.gov number, NCT00403260.).

Mass balance and metabolism of the antimalarial pyronaridine in healthy volunteers.

This was a single dose mass balance and metabolite characterization study of the antimalarial agent pyronaridine. Six healthy male adults were administered a single oral dose of 720 mg pyronaridine tetraphosphate with 800 nCi of radiolabeled (14)C-pyronaridine. Urine and feces were continuously collected through 168 h post-dose, with intermittent 48 h collection periods thereafter through 2064 h post-dose. Drug recovery was computed for analyzed samples and interpolated for intervening time periods in which collection did not occur. Blood samples were obtained to evaluate the pharmacokinetics of total radioactivity and of the parent compound. Total radioactivity in urine, feces, and blood samples was determined by accelerator mass spectrometry (AMS); parent concentrations in blood were determined with LC/MS. Metabolite identification based on blood, urine, and feces samples was conducted using a combination of LC + AMS for identifying radiopeaks, followed by LC/MS/MS for identity confirmation/elucidation. The mean cumulative drug recovery in the urine and feces was 23.7 and 47.8 %, respectively, with an average total recovery of 71.5 %. Total radioactivity was slowly eliminated from blood, with a mean half-life of 33.5 days, substantially longer than the mean parent compound half-life of 5.03 days. Total radioactivity remained detectable in urine and feces collected in the final sampling period, suggesting ongoing elimination. Nine primary and four secondary metabolites of pyronaridine were identified. This study revealed that pyronaridine and its metabolites are eliminated by both the urinary and fecal routes over an extended period of time, and that multiple, varied pathways characterize pyronaridine metabolism.

Pharmacokinetic interaction between pyronaridine-artesunate and metoprolol.

The objectives of this study were to characterize any drug-drug interaction between the antimalarial Pyramax (pyronaridine-artesunate [PA]) and the CYP2D6 probe substrate metoprolol and to assess the safety of 60-day or 90-day PA redosing, particularly with regard to liver biochemistry parameters. Healthy adult subjects were randomized to arm A (n = 26) or arm B (n = 30), with the arm A subjects administered 100 mg metoprolol tartrate in the first period, 100 mg metoprolol tartrate with the third of three daily doses of PA in the second period, and three daily doses of PA alone in the 90-day redosing period. The arm B subjects received the three-day PA regimen in the first period, with redosing of the regimen after 60 days in the second period. The noncompartmental pharmacokinetic parameters were computed for metoprolol, its metabolite alpha-hydroxymetoprolol, and pyronaridine. The coadministration of metoprolol and PA was associated with an average 47.93% (90% confidence interval [CI], 30.52, 67.66) increase in the maximum concentration of metoprolol and a 25.60% (90% CI, 15.78, 36.25) increase in the metoprolol area under the concentration-time curve from time zero to the last quantifiable concentration obtained (AUC0-t); these increases most likely resulted from pyronaridine-mediated CYP2D6 inhibition. No interaction effect of metoprolol with pyronaridine was apparent. Following dosing with PA, some subjects experienced rises in liver function tests above the upper limit of normal during the first few days following PA administration. All such elevations resolved typically within 10 days, and up to 30 days at most. In subjects who were redosed, the incidences of alanine aminotransferase (ALT) or aspartate transaminase (AST) level elevations were similar on the first and second administrations, with no marked difference between the 60-day and 90-day redosing.

Effects of body size and gender on the population pharmacokinetics of artesunate and its active metabolite dihydroartemisinin in pediatric malaria patients.

Despite the important role of the antimalarial artesunate and its active metabolite dihydroartemisinin (DHA) in malaria treatment efforts, there are limited data on the pharmacokinetics of these agents in pediatric patients. This study evaluated the effects of body size and gender on the pharmacokinetics of artesunate-DHA using data from pediatric and adult malaria patients. Nonlinear mixed-effects modeling was used to obtain a base model consisting of first-order artesunate absorption and one-compartment models for artesunate and for DHA. Various methods of incorporating effects of body size descriptors on clearance and volume parameters were tested. An allometric scaling model for weight and a linear body surface area (BSA) model were deemed optimal. The apparent clearance and volume of distribution of DHA obtained with the allometric scaling model, normalized to a 38-kg patient, were 63.5 liters/h and 65.1 liters, respectively. Estimates for the linear BSA model were similar. The 95% confidence intervals for the estimated gender effects on clearance and volume parameters for artesunate fell outside the predefined no-relevant-clinical-effect interval of 0.75 to 1.25. However, the effect of gender on apparent DHA clearance was almost entirely contained within this interval, suggesting a lack of an influence of gender on this parameter. Overall, the pharmacokinetics of artesunate and DHA following oral artesunate administration can be described for pediatric patients using either an allometric scaling or linear BSA model. Both models predict that, for a given artesunate dose in mg/kg of body weight, younger children are expected to have lower DHA exposure than older children or adults.

Safety and efficacy of pyronaridine-artesunate in uncomplicated acute malaria: an integrated analysis of individual patient data from six randomized clinical trials.

BACKGROUND: Pyronaridine-artesunate (PA) is indicated for the treatment of acute uncomplicated Plasmodium falciparum and Plasmodium vivax malaria. METHODS: Individual patient data on safety outcomes were integrated from six randomized clinical trials conducted in Africa and Asia in patients with microscopically confirmed P. falciparum (five studies) or P. vivax (one study) malaria. Efficacy against P. falciparum was evaluated across three Phase III clinical trials. RESULTS: The safety population included 2,815 patients randomized to PA, 1,254 to comparators: mefloquine + artesunate (MQ + AS), artemether-lumefantrine (AL), or chloroquine. All treatments were generally well tolerated. Adverse events occurred in 57.2% (1,611/2,815) of patients with PA versus 51.5% (646/1,254) for comparators, most commonly (PA; comparators): headache (10.6%; 9.9%), cough (5.9%; 5.6%) and anaemia (4.5%; 2.9%). Serious averse events were uncommon for all treatments (0-0.7%). Transient increases in alanine aminotransferase and aspartate aminotransferase were observed with PA but did not lead to any clinical sequelae. For P. falciparum malaria, day-28 PCR-corrected adequate clinical and parasitological response with PA was 93.6% ([1,921/2,052] 95% CI 92.6, 94.7) in the intent-to-treat population and 98.5% ([1,852/1,880] 95% CI 98.0, 99.1) in the per-protocol population. Median parasite clearance time was 24.1 h with PA, 31.9 h with MQ + AS, and 24.0 h with AL. Median fever clearance time was 15.5 h with PA, 15.8 h with MQ + AS, and 14.0 h with AL. By day 42, P. falciparum gametocytes had declined to near zero for all treatments. CONCLUSIONS: Pyronaridine-artesunate was well tolerated with no safety concerns with the exception of mostly mild transient rises in transaminases. Efficacy was high and met the requirements for use as first-line therapy. Pyronaridine-artesunate should be considered for inclusion in malaria treatment programmes. TRIAL REGISTRATION: Clinicaltrials.gov: NCT00331136; NCT00403260; NCT00422084; NCT00440999; NCT00541385; NCT01594931.

Review of pyronaridine anti-malarial properties and product characteristics.

Pyronaridine was synthesized in 1970 at the Institute of Chinese Parasitic Disease and has been used in China for over 30 years for the treatment of malaria. Pyronaridine has high potency against Plasmodium falciparum, including chloroquine-resistant strains. Studies in various animal models have shown pyronaridine to be effective against strains resistant to other anti-malarials, including chloroquine. Resistance to pyronaridine appears to emerge slowly and is further retarded when pyronaridine is used in combination with other anti-malarials, in particular, artesunate. Pyronaridine toxicity is generally less than that of chloroquine, though evidence of embryotoxicity in rodents suggests use with caution in pregnancy. Clinical pharmacokinetic data for pyronaridine indicates an elimination T1/2 of 13.2 and 9.6 days, respectively, in adults and children with acute uncomplicated falciparum and vivax malaria in artemisinin-combination therapy. Clinical data for mono or combined pyronaridine therapy show excellent anti-malarial effects against P. falciparum and studies of combination therapy also show promise against Plasmodium vivax. Pyronaridine has been developed as a fixed dose combination therapy, in a 3:1 ratio, with artesunate for the treatment of acute uncomplicated P. falciparum malaria and blood stage P. vivax malaria with the name of Pyramax® and has received Positive Opinion by European Medicines Agency under the Article 58 procedure.

Pyronaridine-artesunate granules versus artemether-lumefantrine crushed tablets in children with Plasmodium falciparum malaria: a randomized controlled trial.

BACKGROUND: Children are most vulnerable to malaria. A pyronaridine-artesunate pediatric granule formulation is being developed for the treatment of uncomplicated Plasmodium falciparum malaria. METHODS: This phase III, multi-center, comparative, open-label, parallel-group, controlled clinical trial included patients aged ≤12 years, bodyweight ≥5 to <25 kg, with a reported history of fever at inclusion or in the previous 24 h and microscopically-confirmed uncomplicated P. falciparum malaria. Patients were randomized (2:1) to pyronaridine-artesunate granules (60/20 mg) once daily or artemether-lumefantrine crushed tablets (20/120 mg) twice daily, both dosed by bodyweight, orally (liquid suspension) for three days. RESULTS: Of 535 patients randomized, 355 received pyronaridine-artesunate and 180 received artemether-lumefantrine. Day-28 adequate clinical and parasitological response (ACPR), corrected for re-infection using polymerase chain reaction (PCR) genotyping (per-protocol population) was 97.1% (329/339; 95% CI 94.6, 98.6) for pyronaridine-artesunate; 98.8% (165/167; 95% CI 95.7, 99.9) for artemether-lumefantrine. The primary endpoint was achieved: pyronaridine-artesunate PCR-corrected day-28 ACPR was statistically significantly >90% (P < .0001). Pyronaridine-artesunate was non-inferior to artemether-lumefantrine: treatment difference -1.8% (95% CI -4.3 to 1.6). The incidence of drug-related adverse events was 37.2% (132/355) with pyronaridine-artesunate, 44.4% (80/180) with artemether-lumefantrine. Clinical biochemistry results showed similar mean changes versus baseline in the two treatment groups. From day 3 until study completion, one patient in each treatment group had peak alanine aminotransferase (ALT) >3 times the upper limit of normal (ULN) and peak total bilirubin >2xULN (i.e. within the Hy's law definition). CONCLUSIONS: The pyronaridine-artesunate pediatric granule formulation was efficacious and was non-inferior to artemether-lumefantrine. The adverse event profile was similar for the two comparators. Pyronaridine-artesunate should be considered for inclusion in paediatric malaria treatment programmes. TRIAL REGISTRATION: ClinicalTrials.gov: identifier NCT00541385.

Pharmacokinetics of oral moxidectin in individuals with Onchocerca volvulus infection.

BACKGROUND: Onchocerciasis ("river blindness"), is a neglected tropical disease caused by the filarial nematode Onchocerca volvulus and transmitted to humans through repeated bites by infective blackflies of the genus Simulium. Moxidectin was approved by the United States Food and Drug Administration in 2018 for the treatment of onchocerciasis in people at least 12 years of age. The pharmacokinetics of orally administered moxidectin in 18- to 60-year-old men and women infected with Onchocerca volvulus were investigated in a single-center, ivermectin-controlled, double-blind, randomized, single-ascending-dose, ascending severity of infection study in Ghana. METHODOLOGY/PRINCIPAL FINDINGS: Participants were randomized to either a single dose of 2, 4 or 8 mg moxidectin or ivermectin. Pharmacokinetic samples were collected prior to dosing and at intervals up to 12 months post-dose from 33 and 34 individuals treated with 2 and 4 mg moxidectin, respectively and up to 18 months post-dose from 31 individuals treated with 8 mg moxidectin. Moxidectin plasma concentrations were determined using high-performance liquid chromatography with fluorescence detection. Moxidectin plasma AUC0-∞ (2 mg: 26.7-31.7 days*ng/mL, 4 mg: 39.1-60.0 days*ng/mL, 8 mg: 99.5-129.0 days*ng/mL) and Cmax (2mg, 16.2 to17.3 ng/mL, 4 mg: 33.4 to 35.0 ng/mL, 8 mg: 55.7 to 74.4 ng/mL) were dose-proportional and independent of severity of infection. Maximum plasma concentrations were achieved 4 hours after drug administration. The mean terminal half-lives of moxidectin were 20.6, 17.7, and 23.3 days at the 2, 4 and 8 mg dose levels, respectively. CONCLUSION/SIGNIFICANCE: We found no relationship between severity of infection (mild, moderate or severe) and exposure parameters (AUC0-∞ and Cmax), T1/2 and Tmax for moxidectin. Tmax, volume of distribution (V/F) and oral clearance (CL/F) are similar to those in healthy volunteers from Europe. From a pharmacokinetic perspective, moxidectin is an attractive long-acting therapeutic option for the treatment of human onchocerciasis.

Excretion of moxidectin into breast milk and pharmacokinetics in healthy lactating women.

Moxidectin, registered worldwide as a veterinary antiparasitic agent, is currently under development for humans for the treatment of onchocerciasis in collaboration with the World Health Organization. The objective of this study was to assess the pharmacokinetics of moxidectin in healthy lactating women, including the excretion into breast milk. Twelve women, ages 23 to 38 years, weighing 54 to 79 kg, all more than 5 months postpartum, were enrolled, following their plan to wean their infants and provision of informed consent. A single 8-mg, open-label dose was administered orally after consumption of a standard breakfast. Complete milk collection was done for approximately 28 days, and plasma samples were collected for 90 days. Moxidectin concentrations were measured by high-performance liquid chromatography (HPLC) with fluorescence detection, with a validated range of 0.08 to 120 ng/ml. Noncompartmental pharmacokinetic methods were used to find the following results: peak concentration in plasma (C(max)), 87 ± 25 ng/ml; time to C(max) (t(max)), 4.18 ± 1.59 h; terminal-phase elimination half-life (t(1/2)), 832 ± 321 h; total area under the concentration-time curve (AUC), 4,046 ± 1,796 ng · h/ml; apparent oral dose clearance (CL/F), 2.35 ± 1.07 l/h; ratio of CL/F to the terminal-phase disposition rate constant, λ(z) (Vλ(z)/F), 2,526 ± 772 liters; percentage of maternal dose excreted in milk, 0.701 ± 0.299%; absolute amount excreted in milk, 0.056 ± 0.024 mg; relative infant dose, 8.73 ± 3.17% of maternal dose assuming complete absorption; clearance in milk (CL(milk)), 0.016 ± 0.009 liter/h. Nine of 12 subjects reported adverse events, all of which were considered treatment emergent but not drug related and were mostly reported during the long outpatient period 8 to 90 days after dose administration. The most frequently reported adverse events were headache and nausea (n = 4), oropharyngeal pain (n = 2), rhinitis, viral pharyngitis, and viral upper respiratory tract infection (n = 2).

Efficacy and safety of a fixed-dose oral combination of pyronaridine-artesunate compared with artemether-lumefantrine in children and adults with uncomplicated Plasmodium falciparum malaria: a randomised non-inferiority trial.

BACKGROUND: There is a need for new artemisinin-based combination therapies that are convenient, effective, and safe. We compared the efficacy and safety of pyronaridine-artesunate with that of artemether-lumefantrine for treatment of uncomplicated P falciparum malaria. METHODS: This phase 3, parallel-group, double-blind, randomised, non-inferiority trial was undertaken in seven sites in Africa and three sites in southeast Asia. In a double-dummy design, patients aged 3-60 years with uncomplicated P falciparum malaria were randomly assigned in a 2:1 ratio to receive pyronaridine-artesunate once a day or artemether-lumefantrine twice a day, orally for 3 days, plus respective placebo. Randomisation was done by computer-generated randomisation sequence in blocks of nine by study centre. Intervention tablets contained 180 mg pyronaridine and 60 mg artesunate; control tablets contained 20 mg artemether and 120 mg lumefantrine. Both treatments were given according to bodyweight. The primary efficacy outcome was PCR-corrected adequate clinical and parasitological response (ACPR) rate at day 28 in the per-protocol population. Non-inferiority was shown if the lower limit of the two-sided 95% CI for the difference between groups was greater than -5%. This study is registered with ClinicalTrials.gov, number NCT00422084. FINDINGS: 1272 patients were randomly assigned to treatment (pyronaridine-artesunate, n=849; artemether-lumefantrine, n=423). The per-protocol population consisted of 784 patients in the pyronaridine-artesunate group and 386 patients in the artemether-lumefantrine group. PCR-corrected ACPR rate at day 28 was 99.5% (780 patients; 95% CI 98.7-99.9) in the pyronaridine-artesunate group and 99.2% (383 patients; 95% CI 97.7-99.8) in the artemether-lumefantrine group (treatment difference 0.3%, 95% CI -0.7 to 1.8; p=0.578). There were 509 (60.0%) adverse events in 849 patients assigned to pyronaridine-artesunate and 241 (57.0%) in 423 patients assigned to artemether-lumefantrine. The most frequent drug-related adverse event was eosinophilia (pyronaridine-artesunate, 53 events [6.2%]; artemether-lumefantrine 24 events [5.7%]). 21 (2.5%) patients in the pyronaridine-artesunate group and seven (1.7%) in the artemether-lumefantrine group discontinued study drugs or were withdrawn from the study. Mild and transient increases in alanine aminotransferase and aspartate aminotransferase concentrations were seen in the pyronaridine-artesunate group but not in the artemether-lumefantrine group. INTERPRETATION: Efficacy of pyronaridine-artesunate was non-inferior to that of artemether-lumefantrine for treatment of uncomplicated falciparum malaria. Pyronaridine-artesunate should be considered for inclusion in malaria treatment programmes. FUNDING: Shin Poong Pharmaceutical and the Medicines for Malaria Venture.

Review of the clinical pharmacokinetics of artesunate and its active metabolite dihydroartemisinin following intravenous, intramuscular, oral or rectal administration.

Artesunate (AS) is a clinically versatile artemisinin derivative utilized for the treatment of mild to severe malaria infection. Given the therapeutic significance of AS and the necessity of appropriate AS dosing, substantial research has been performed investigating the pharmacokinetics of AS and its active metabolite dihydroartemisinin (DHA). In this article, a comprehensive review is presented of AS clinical pharmacokinetics following administration of AS by the intravenous (IV), intramuscular (IM), oral or rectal routes. Intravenous AS is associated with high initial AS concentrations which subsequently decline rapidly, with typical AS half-life estimates of less than 15 minutes. AS clearance and volume estimates average 2 - 3 L/kg/hr and 0.1 - 0.3 L/kg, respectively. DHA concentrations peak within 25 minutes post-dose, and DHA is eliminated with a half-life of 30 - 60 minutes. DHA clearance and volume average between 0.5 - 1.5 L/kg/hr and 0.5 - 1.0 L/kg, respectively. Compared to IV administration, IM administration produces lower peaks, longer half-life values, and higher volumes of distribution for AS, as well as delayed peaks for DHA; other parameters are generally similar due to the high bioavailability, assessed by exposure to DHA, associated with IM AS administration (> 86%). Similarly high bioavailability of DHA (> 80%) is associated with oral administration. Following oral AS, peak AS concentrations (Cmax) are achieved within one hour, and AS is eliminated with a half-life of 20 - 45 minutes. DHA Cmax values are observed within two hours post-dose; DHA half-life values average 0.5 - 1.5 hours. AUC values reported for AS are often substantially lower than those reported for DHA following oral AS administration. Rectal AS administration yields pharmacokinetic results similar to those obtained from oral administration, with the exceptions of delayed AS Cmax and longer AS half-life. Drug interaction studies conducted with oral AS suggest that AS does not appreciably alter the pharmacokinetics of atovaquone/proguanil, chlorproguanil/dapsone, or sulphadoxine/pyrimethamine, and mefloquine and pyronaridine do not alter the pharmacokinetics of DHA. Finally, there is evidence suggesting that the pharmacokinetics of AS and/or DHA following AS administration may be altered by pregnancy and by acute malaria infection, but further investigation would be required to define those alterations precisely.

Population pharmacokinetics of artesunate and dihydroartemisinin in pregnant and non-pregnant women with malaria.

BACKGROUND: The World Health Organization endorses the use of artemisinin-based combination therapy for treatment of acute uncomplicated falciparum malaria in the second and third trimesters of pregnancy. However, the effects of pregnancy on the pharmacokinetics of artemisinin derivatives, such as artesunate (AS), are poorly understood. In this analysis, the population pharmacokinetics of oral AS, and its active metabolite dihydroartemisinin (DHA), were studied in pregnant and non-pregnant women at the Kingasani Maternity Clinic in the DRC. METHODS: Data were obtained from 26 pregnant women in the second (22-26 weeks) or the third (32-36 weeks) trimester of pregnancy and from 25 non-pregnant female controls. All subjects received 200 mg AS. Plasma AS and DHA were measured using a validated LC-MS method. Estimates for pharmacokinetic and variability parameters were obtained through nonlinear mixed effects modelling. RESULTS: A simultaneous parent-metabolite model was developed consisting of mixed zero-order, lagged first-order absorption of AS, a one-compartment model for AS, and a one-compartment model for DHA. Complete conversion of AS to DHA was assumed. The model displayed satisfactory goodness-of-fit, stability, and predictive ability. Apparent clearance (CL/F) and volume of distribution (V/F) estimates, with 95% bootstrap confidence intervals, were as follows: 195 L (139-285 L) for AS V/F, 895 L/h (788-1045 L/h) for AS CL/F, 91.4 L (78.5-109 L) for DHA V/F, and 64.0 L/h (55.1-75.2 L/h) for DHA CL/F. The effect of pregnancy on DHA CL/F was determined to be significant, with a pregnancy-associated increase in DHA CL/F of 42.3% (19.7-72.3%). CONCLUSIONS: In this analysis, pharmacokinetic modelling suggests that pregnant women have accelerated DHA clearance compared to non-pregnant women receiving orally administered AS. These findings, in conjunction with a previous non-compartmental analysis of the modelled data, provide further evidence that higher AS doses would be required to maintain similar DHA levels in pregnant women as achieved in non-pregnant controls.

Pharmacokinetics and pharmacodynamics of artesunate and dihydroartemisinin following oral treatment in pregnant women with asymptomatic Plasmodium falciparum infections in Kinshasa DRC.

BACKGROUND: In many malaria-endemic countries, increasing resistance may soon compromise the efficacy of sulphadoxine-pyrimethamine (SP) for intermittent preventative treatment (IPT) of malaria in pregnancy. Artemisinin-based IPT regimens represent a promising potential alternative to SP. Pharmacokinetic and safety data supporting the use of artemisinin derivatives in pregnancy are urgently needed. METHODS: Subjects included pregnant women with asymptomatic falciparum parasitaemia between 22-26 weeks (n = 13) or 32-36 weeks gestation (n = 13), the same women at three months postpartum, and 25 non-pregnant parasitaemic controls. All subjects received 200 mg orally administered AS. Plasma total and free levels of AS and its active metabolite DHA were determined using a validated LC-MS method. Non-compartmental pharmacokinetic analysis was performed using standard methods. RESULTS: All pregnant women delivered live babies. The median birth weight was 3025 grams [range 2130, 3620]; 2 of 26 babies had birth weights less than 2500 grams. Rates of parasite clearance by 12 hours post-dose were high and comparable among the groups. Rapid elimination of AS was observed in all three groups. The 90% CI for the pregnancy:postpartum ratio of geometric means for total and free AUC fell within the pre-specified 0.66 - 1.50 therapeutic equivalence interval. However, more pronounced pharmacokinetic differences were observed between the pregnancy and control subjects, with the 90% CI for the pregnancy:control ratio of geometric means for both total 0.68 (90% CI 0.57-0.81) and free AUC 0.78 (90% CI 0.63-0.95) not fully contained within the 0.66 - 1.50 interval. All subjects cleared parasites rapidly, and there was no difference in the percentage of women who were parasitaemic 12 hours after dosing. CONCLUSIONS: A single dose of orally administered AS was found to be both effective and without adverse effects in this study of second and third trimester pregnant women in the DRC. Although DHA AUC during pregnancy and postpartum were similar, the AUC for the pregnant group was less than the non-pregnant controls. The findings of this study suggest that additional studies on the pharmacokinetics of AS in pregnant women are needed. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00538382.

Serum ivermectin levels after enteral and subcutaneous administration for Strongyloides hyperinfection: a case report.

An AIDS patient was diagnosed with Strongyloides stercoralis hyperinfection complicated by ileus. Serum ivermectin concentrations were very low after rectal administration, but increased after subcutaneous doses. Absorption of rectal ivermectin appears poor, and subcutaneous administration can increase serum levels quickly, which may improve treatment in critically ill patients.

Population pharmacokinetics of artesunate and dihydroartemisinin following single- and multiple-dosing of oral artesunate in healthy subjects.

BACKGROUND: The population pharmacokinetics of artesunate (AS) and its active metabolite dihydroartemisinin (DHA) were studied in healthy subjects receiving single- or multiple-dosing of AS orally either in combination with pyronaridine (PYR) or as a monotherapy with or without food. METHODS: Data from 118 concentration-time profiles arising from 91 healthy Korean subjects were pooled from four Phase I clinical studies. Subjects received 2-5 mg/kg of single- and multiple-dosing of oral AS either in combination with PYR or as a monotherapy with or without food. Plasma AS and DHA were measured simultaneously using a validated liquid chromatography- mass spectrometric method with a lower limit of quantification of 1 ng/mL for both AS and DHA. Nonlinear mixed-effect modelling was used to obtain the pharmacokinetic and variability (inter-individual and residual variability) parameter estimates. RESULTS: A novel parent-metabolite pharmacokinetic model consisting of a dosing compartment, a central compartment for AS, a central compartment and a peripheral compartment for DHA was developed. AS and DHA data were modelled simultaneously assuming stoichiometric conversion to DHA. AS was rapidly absorbed with a population estimate of absorption rate constant (Ka) of 3.85 h-1. The population estimates of apparent clearance (CL/F) and volume of distribution (V2/F) for AS were 1190 L/h with 36.2% inter-individual variability (IIV) and 1210 L with 57.4% IIV, respectively. For DHA, the population estimates of apparent clearance (CLM/F) and central volume of distribution (V3/F) were 93.7 L/h with 28% IIV and 97.1 L with 30% IIV, respectively. The population estimates of apparent inter-compartmental clearance (Q/F) and peripheral volume of distribution (V4/F) for DHA were 5.74 L/h and 18.5 L, respectively. Intake of high-fat and high-caloric meal prior to the drug administration resulted in 84% reduction in Ka. Body weight impacted CLM/F, such that a unit change in weight resulted in 1.9-unit change in CLM/F in the same direction. CONCLUSIONS: A novel simultaneous parent-metabolite pharmacokinetic model with good predictive power was developed to study the population pharmacokinetics of AS and DHA in healthy subjects following single- and multiple-dosing of AS with or without the presence of food. Food intake and weight were significant covariates for Ka and CLM/F, respectively.

Development and validation of a liquid chromatography-mass spectrometry assay for the determination of pyronaridine in human urine.

A reliable method has been developed for the determination of pyronaridine in human urine using amodiaquine as an internal standard. Liquid-liquid extraction was used for sample preparation. Analysis was performed on a Shimadzu LCMS-2010 in single ion monitoring positive mode using atmospheric pressure chemical ionization (APCI) as an interface. The extracted ion for pyronaridine was m/z 518.20 and for amodiaquine was m/z 356.10. Chromatography was carried out using a Gemini 5 microm C18 3.0 mmx150 mm column using 2 mM perflurooctanoic acid and acetonitrile mixture as a mobile phase delivered at a flow rate of 0.5 mL/min. The mobile phase was delivered in gradient mode. The retention times of pyronaridine and amodiaquine were 9.1 and 8.1 min respectively, with a total run time of 14 min. The assay was linear over a range of 14.3-1425 ng/mL for pyronaridine (R2>or=0.992, weighted 1/Concentration). The analysis of quality control samples for pyronaridine at 28.5, 285, 684 and 1140 ng/mL demonstrated excellent precision with relative standard deviation of 5.1, 2.3, 3.9 and 9.2%, respectively (n=5). Recoveries at concentrations of 28.5, 285, 684 and 1140 ng/mL were all greater than 85%. This LC-MS method for the determination of pyronaridine in human urine has excellent specifications for sensitivity, reproducibility and accuracy and can reliably quantitate concentrations of pyronaridine in urine as low as 14.3 ng/mL. The method will be used to quantify pyronaridine in human urine for pharmacokinetic and drug safety studies.