Leishmania blood parasite dynamics during and after treatment of visceral leishmaniasis in Eastern Africa: A pharmacokinetic-pharmacodynamic model.

BACKGROUND: With the current treatment options for visceral leishmaniasis (VL), recrudescence of the parasite is seen in a proportion of patients. Understanding parasite dynamics is crucial to improving treatment efficacy and predicting patient relapse in cases of VL. This study aimed to characterize the kinetics of circulating Leishmania parasites in the blood, during and after different antileishmanial therapies, and to find predictors for clinical relapse of disease. METHODS: Data from three clinical trials, in which Eastern African VL patients received various antileishmanial regimens, were combined in this study. Leishmania kinetoplast DNA was quantified in whole blood with real-time quantitative PCR (qPCR) before, during, and up to six months after treatment. An integrated population pharmacokinetic-pharmacodynamic model was developed using non-linear mixed effects modelling. RESULTS: Parasite proliferation was best described by an exponential growth model, with an in vivo parasite doubling time of 7.8 days (RSE 12%). Parasite killing by fexinidazole, liposomal amphotericin B, sodium stibogluconate, and miltefosine was best described by linear models directly relating drug concentrations to the parasite elimination rate. After treatment, parasite growth was assumed to be suppressed by the host immune system, described by an Emax model driven by the time after treatment. No predictors for the high variability in onset and magnitude of the immune response could be identified. Model-based individual predictions of blood parasite load on Day 28 and Day 56 after start of treatment were predictive for clinical relapse of disease. CONCLUSION: This semi-mechanistic pharmacokinetic-pharmacodynamic model adequately captured the blood parasite dynamics during and after treatment, and revealed that high blood parasite loads on Day 28 and Day 56 after start of treatment are an early indication for VL relapse, which could be a useful biomarker to assess treatment efficacy of a treatment regimen in a clinical trial setting.

Dose rationale for gabapentin and tramadol in pediatric patients with chronic pain.

Despite off-label use, the efficacy and safety of gabapentin and tramadol in pediatric patients (3 months to <18 years old) diagnosed with chronic pain has not been characterized. However, generating evidence based on randomized clinical trials in this population has been extremely challenging. The current investigation illustrates the use of clinical trial simulations (CTSs) as a tool for optimizing doses and protocol design for a prospective investigation in pediatric patients with chronic pain. Pharmacokinetic (PK) modeling and CTSs were used to describe the PKs of gabapentin and tramadol in the target population. In the absence of biomarkers of analgesia, systemic exposure (AUC, Css) was used to guide dose selection under the assumption of a comparable exposure-response (PKPD) relationship for either compound between adults and children. Two weight bands were identified for gabapentin, with doses titrated from 5 to 63 mg/kg. This yields gabapentin exposures (AUC0-8 ) of approximately 35 mg/L*h (1200 mg/day adult dose equivalent). For tramadol, median steady state concentrations between 200 and 300 ng/mL were achieved after doses of 2-5 mg/kg, but concentrations showed high interindividual variability. Simulation scenarios showed that titration steps are required to explore therapeutically relevant dose ranges taking into account the safety profile of both drugs. Gabapentin can be used t.i.d. at doses between 7-63 and 5-45 mg/kg for patients receiving gabapentin weighing <15 and ≥15 kg, respectively, whereas a t.i.d. regimen with doses between 1 and 5 mg/kg can be used for tramadol in patients who are not fast metabolisers.

Population pharmacokinetics of a combination of miltefosine and paromomycin in Eastern African children and adults with visceral leishmaniasis.

OBJECTIVES: To improve visceral leishmaniasis (VL) treatment in Eastern Africa, 14- and 28-day combination regimens of paromomycin plus allometrically dosed miltefosine were evaluated. As the majority of patients affected by VL are children, adequate paediatric exposure to miltefosine and paromomycin is key to ensuring good treatment response. METHODS: Pharmacokinetic data were collected in a multicentre randomized controlled trial in VL patients from Kenya, Sudan, Ethiopia and Uganda. Patients received paromomycin (20 mg/kg/day for 14 days) plus miltefosine (allometric dose for 14 or 28 days). Population pharmacokinetic models were developed. Adequacy of exposure and target attainment of paromomycin and miltefosine were evaluated in children and adults. RESULTS: Data from 265 patients (59% ≤12 years) were available for this pharmacokinetic analysis. Paromomycin exposure was lower in paediatric patients compared with adults [median (IQR) end-of-treatment AUC0-24h 187 (162-203) and 242 (217-328) µg·h/mL, respectively], but were both within the IQR of end-of-treatment exposure in Kenyan and Sudanese adult patients from a previous study. Cumulative miltefosine end-of-treatment exposure in paediatric patients and adults [AUCD0-28 517 (464-552) and 524 (456-567) µg·day/mL, respectively] and target attainment [time above the in vitro susceptibility value EC90 27 (25-28) and 30 (28-32) days, respectively] were comparable to previously observed values in adults. CONCLUSIONS: Paromomycin and miltefosine exposure in this new combination regimen corresponded to the desirable levels of exposure, supporting the implementation of the shortened 14 day combination regimen. Moreover, the lack of a clear exposure-response and exposure-toxicity relationship indicated adequate exposure within the therapeutic range in the studied population, including paediatric patients.

Paromomycin and Miltefosine Combination as an Alternative to Treat Patients With Visceral Leishmaniasis in Eastern Africa: A Randomized, Controlled, Multicountry Trial.

BACKGROUND: This study aimed to determine whether paromomycin plus miltefosine (PM/MF) is noninferior to sodium stibogluconate plus paromomycin (SSG/PM) for treatment of primary visceral leishmaniasis in eastern Africa. METHODS: An open-label, phase 3, randomized, controlled trial was conducted in adult and pediatric patients at 7 sites in eastern Africa. Patients were randomly assigned to either 20 mg/kg paromomycin plus allometric dose of miltefosine (14 days), or 20 mg/kg sodium stibogluconate plus 15 mg/kg paromomycin (17 days). The primary endpoint was definitive cure after 6 months. RESULTS: Of 439 randomized patients, 424 completed the trial. Definitive cure at 6 months was 91.2% (155 of 170) and 91.8% (156 of 170) in the PM/MF and SSG/PM arms in primary efficacy modified intention-to-treat analysis (difference, 0.6%; 97.5% confidence interval [CI], -6.2 to 7.4), narrowly missing the noninferiority margin of 7%. In the per-protocol analysis, efficacy was 92% (149 of 162) and 91.7% (155 of 169) in the PM/MF and SSG/PM arms (difference, -0.3%; 97.5% CI, -7.0 to 6.5), demonstrating noninferiority. Treatments were well tolerated. Four of 18 serious adverse events were study drug-related, and 1 death was SSG-related. Allometric dosing ensured similar MF exposure in children (<12 years) and adults. CONCLUSIONS: PM/MF and SSG/PM efficacies were similar, and adverse drug reactions were as expected given the drugs safety profiles. With 1 less injection each day, reduced treatment duration, and no risk of SSG-associated life-threatening cardiotoxicity, PM/MF is a more patient-friendly alternative for children and adults with primary visceral leishmaniasis in eastern Africa. CLINICAL TRIALS REGISTRATION: NCT03129646.

Geographical Variability in Paromomycin Pharmacokinetics Does Not Explain Efficacy Differences between Eastern African and Indian Visceral Leishmaniasis Patients.

INTRODUCTION: Intramuscular paromomycin monotherapy to treat visceral leishmaniasis (VL) has been shown to be effective for Indian patients, while a similar regimen resulted in lower efficacy in Eastern Africa, which could be related to differences in paromomycin pharmacokinetics. METHODS: Pharmacokinetic data were available from two randomized controlled trials in VL patients from Eastern Africa and India. African patients received intramuscular paromomycin monotherapy (20 mg/kg for 21 days) or combination therapy (15 mg/kg for 17 days) with sodium stibogluconate. Indian patients received paromomycin monotherapy (15 mg/kg for 21 days). A population pharmacokinetic model was developed for paromomycin in Eastern African and Indian VL patients. RESULTS: Seventy-four African patients (388 observations) and 528 Indian patients (1321 observations) were included in this pharmacokinetic analysis. A one-compartment model with first-order kinetics of absorption and elimination best described paromomycin in plasma. Bioavailability (relative standard error) was 1.17 (5.18%) times higher in Kenyan and Sudanese patients, and 2.46 (24.5%) times higher in Ethiopian patients, compared with Indian patients. Ethiopian patients had an approximately fourfold slower absorption rate constant of 0.446 h-1 (18.2%). Area under the plasma concentration-time curve for 24 h at steady-state (AUCτ,SS) for 15 mg/kg/day (median [interquartile range]) was higher in Kenya and Sudan (172.7 µg·h/mL [145.9-214.3]) and Ethiopia (230.1 µg·h/mL [146.3-591.2]) compared with India (97.26 µg·h/mL [80.83-123.4]). CONCLUSION: The developed model provides detailed insight into the pharmacokinetic differences among Eastern African countries and India, however the resulting differences in paromomycin exposure do not seem to explain the geographical differences in paromomycin efficacy in the treatment of VL patients.

Influence of Malnutrition on the Pharmacokinetics of Drugs Used in the Treatment of Poverty-Related Diseases: A Systematic Review.

BACKGROUND: Patients affected by poverty-related infectious diseases (PRDs) are disproportionally affected by malnutrition. To optimize treatment of patients affected by PRDs, we aimed to assess the influence of malnutrition associated with PRDs on drug pharmacokinetics, by way of a systematic review. METHODS: A systematic review was performed on the effects of malnourishment on the pharmacokinetics of drugs to treat PRDs, including HIV, tuberculosis, malaria, and neglected tropical diseases. RESULTS: In 21/29 PRD drugs included in this review, pharmacokinetics were affected by malnutrition. Effects were heterogeneous, but trends were observed for specific classes of drugs and different types and degrees of malnutrition. Bioavailability of lumefantrine, sulfadoxine, pyrimethamine, lopinavir, and efavirenz was decreased in severely malnourished patients, but increased for the P-glycoprotein substrates abacavir, saquinavir, nevirapine, and ivermectin. Distribution volume was decreased for the lipophilic drugs isoniazid, chloroquine, and nevirapine, and the α1-acid glycoprotein-bound drugs quinine, rifabutin, and saquinavir. Distribution volume was increased for the hydrophilic drug streptomycin and the albumin-bound drugs rifampicin, lopinavir, and efavirenz. Drug elimination was decreased for isoniazid, chloroquine, quinine, zidovudine, saquinavir, and streptomycin, but increased for the albumin-bound drugs quinine, chloroquine, rifampicin, lopinavir, efavirenz, and ethambutol. Clinically relevant effects were mainly observed in severely malnourished and kwashiorkor patients. CONCLUSIONS: Malnutrition-related effects on pharmacokinetics potentially affect treatment response, particularly for severe malnutrition or kwashiorkor. However, pharmacokinetic knowledge is lacking for specific populations, especially patients with neglected tropical diseases and severe malnutrition. To optimize treatment in these neglected subpopulations, adequate pharmacokinetic studies are needed, including severely malnourished or kwashiorkor patients.

Blood Parasite Load as an Early Marker to Predict Treatment Response in Visceral Leishmaniasis in Eastern Africa.

BACKGROUND: To expedite the development of new oral treatment regimens for visceral leishmaniasis (VL), there is a need for early markers to evaluate treatment response and predict long-term outcomes. METHODS: Data from 3 clinical trials were combined in this study, in which Eastern African VL patients received various antileishmanial therapies. Leishmania kinetoplast DNA was quantified in whole blood with real-time quantitative polymerase chain reaction (qPCR) before, during, and up to 6 months after treatment. The predictive performance of pharmacodynamic parameters for clinical relapse was evaluated using receiver-operating characteristic curves. Clinical trial simulations were performed to determine the power associated with the use of blood parasite load as a surrogate endpoint to predict clinical outcome at 6 months. RESULTS: The absolute parasite density on day 56 after start of treatment was found to be a highly sensitive predictor of relapse within 6 months of follow-up at a cutoff of 20 parasites/mL (area under the curve 0.92, specificity 0.91, sensitivity 0.89). Blood parasite loads correlated well with tissue parasite loads (ρ = 0.80) and with microscopy gradings of bone marrow and spleen aspirate smears. Clinical trial simulations indicated a > 80% power to detect a difference in cure rate between treatment regimens if this difference was high (> 50%) and when minimally 30 patients were included per regimen. CONCLUSIONS: Blood Leishmania parasite load determined by qPCR is a promising early biomarker to predict relapse in VL patients. Once optimized, it might be useful in dose finding studies of new chemical entities.

Association between anti-thymocyte globulin exposure and survival outcomes in adult unrelated haemopoietic cell transplantation: a multicentre, retrospective, pharmacodynamic cohort analysis.

BACKGROUND: Anti-thymocyte globulin (ATG) is used to prevent graft-versus-host disease (GvHD) after allogeneic haemopoietic cell transplantation (HCT). However, ATG can also cause delayed immune reconstitution of T cells, negatively affecting survival. We studied the relation between exposure to ATG and clinical outcomes in adult patients with acute leukaemia and myelodysplastic syndrome. METHODS: We did a retrospective, pharmacokinetic-pharmacodynamic analysis of data from patients with acute lymphoid leukaemia, acute myeloid leukaemia, or myelodysplastic syndrome receiving their first T-cell repleted allogeneic peripheral blood stem cell HCT with ATG (thymoglobulin) as part of non-myeloablative conditioning from March 1, 2004, to June 1, 2015. Patients received a cumulative intravenous dose of 8 mg/kg divided over 4 days, starting on day -8 before HCT. Active ATG concentrations were measured using a validated bioassay and pharmacokinetic exposure measures (maximum concentration, concentration at time of infusion of the graft, time to reach a concentration of 1 arbitary unit [AU] per day/mL, area under the curve [AUC], and the AUC before and after HCT) were calculated with a validated population pharmacokinetic model. The main outcome of interest was 5-year overall survival, defined as days to death from any cause or last follow-up. Other outcomes were relapse-related mortality, non-relapse mortality, event-free survival, acute and chronic GvHD, and assessment of current and optimum dosing. We used Cox proportional hazard models and Fine-Gray competing risk models for the analyses. FINDINGS: 146 patients were included. ATG exposure after HCT was shown to be the best predictor for 5-year overall survival. Optimum exposure after transplantation was determined to be 60-95 AU per day/mL. Estimated 5-year overall survival in the group who had optimum exposure (69%, 95% CI 55-86) was significantly higher than in the group who had below optimum exposure (32%, 20-51, p=0·00037; hazard ratio [HR] 2·41, 95% CI 1·15-5·06, p=0·020) and above optimum exposure (48%, 37-62, p=0·030; HR 2·11, 95% CI 1·04-4·27, p=0·038). Patients in the optimum exposure group had a greater chance of event-free survival than those in the below optimum exposure group (HR 2·54, 95% CI 1·29-5·00, p=0·007; HR for the above optimum group: 1·83, 0·97-3·47, p=0·063). Above-optimum exposure led to higher relapse-related mortality compared with optimum exposure (HR 2·66, 95% CI 1·12-6·31; p=0·027). Below optimum exposure increased non-relapse mortality compared with optimum exposure (HR 4·36, 95% CI 1·60-11·88; p=0·0040), grade 3-4 acute GvHD (3·09, 1·12-8·53; p=0·029), but not chronic GvHD (2·38, 0·93-6·08; p=0·070). Modelled dosing based on absolute lymphocyte counts led to higher optimum target attainment than did weight-based dosing. INTERPRETATION: Exposure to ATG affects survival after HCT in adults, stressing the importance of optimum ATG dosing. Individualised dosing of ATG, based on lymphocyte counts rather than bodyweight, might improve survival chances after HCT. FUNDING: Netherlands Organization for Health Research and Development and Queen Wilhelma Fund for Cancer Research.

Lack of Clinical Pharmacokinetic Studies to Optimize the Treatment of Neglected Tropical Diseases: A Systematic Review.

INTRODUCTION: Neglected tropical diseases (NTDs) affect more than one billion people, mainly living in developing countries. For most of these NTDs, treatment is suboptimal. To optimize treatment regimens, clinical pharmacokinetic studies are required where they have not been previously conducted to enable the use of pharmacometric modeling and simulation techniques in their application, which can provide substantial advantages. OBJECTIVES: Our aim was to provide a systematic overview and summary of all clinical pharmacokinetic studies in NTDs and to assess the use of pharmacometrics in these studies, as well as to identify which of the NTDs or which treatments have not been sufficiently studied. METHODS: PubMed was systematically searched for all clinical trials and case reports until the end of 2015 that described the pharmacokinetics of a drug in the context of treating any of the NTDs in patients or healthy volunteers. RESULTS: Eighty-two pharmacokinetic studies were identified. Most studies included small patient numbers (only five studies included >50 subjects) and only nine (11 %) studies included pediatric patients. A large part of the studies was not very recent; 56 % of studies were published before 2000. Most studies applied non-compartmental analysis methods for pharmacokinetic analysis (62 %). Twelve studies used population-based compartmental analysis (15 %) and eight (10 %) additionally performed simulations or extrapolation. For ten out of the 17 NTDs, none or only very few pharmacokinetic studies could be identified. CONCLUSIONS: For most NTDs, adequate pharmacokinetic studies are lacking and population-based modeling and simulation techniques have not generally been applied. Pharmacokinetic clinical trials that enable population pharmacokinetic modeling are needed to make better use of the available data. Simulation-based studies should be employed to enable the design of improved dosing regimens and more optimally use the limited resources to effectively provide therapy in this neglected area.