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

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.This work was supported by the European Union Seventh Framework Programme Africoleish (grant number 305178); the World Health Organization—Special Programme for Research and Training in Tropical Diseases (WHO-TDR); the French Development Agency, France (grant number CZZ2062); UK aid, UK; the Federal Ministry of Education and Research through KfW, Germany; the Medicor Foundation, Liechtenstein; Médecins Sans Frontières, International; the Swiss Agency for Development and Cooperation (SDC), Switzerland (grant number 81017718); the Dutch Ministry of Foreign Affairs (DGIS), the Netherlands (grant number PDP15CH21); the French Ministry for Europe and Foreign Affairs (MEAE), France; The Rockefeller Foundation, USA; BBVA Foundation, Spain; the European Union—AfriKADIA project of the Second European and Developing Countries Clinical Trials Partnership Programme (EDCTP2) (grant number RIA2016S1635); and ZonMw/Dutch Research Council (NWO) Veni grant (project number 91617140 to T. P. C. D.).S

Leishmania blood parasite dynamics during and after treatment of visceral leishmaniasis in Eastern Africa: A pharmacokineticpharmacodynamic 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 antil-eishmanial 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. (grant agreement 305178); the World Health Organization-Special Programme for Research and Training in Tropical Diseases (WHO-TDR); the French Development Agency (AFD), France (grant number CZZ2062); UK aid, UK; the Federal Ministry of Education and Research (BMBF) through KfW, Germany; the Medicor Foundation; Médecins Sans Frontières International; the Swiss Agency for Development and Cooperation, Switzerland (grant number 81017718 and 642.33/2010/0779/02 NID); the Dutch Ministry of Foreign Affairs, the Netherlands (grant number PDP15CH21); the Spanish Agency for International Development Cooperation (AECID) and other private foundations and individuals. T.P.C.D. is personally supported by the ZonMw/Dutch Research Council (NWO) Veni grant (project no. 91617140) and the Swedish Research Council (VR 2022-01251). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

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

Disease-Specific Differences in Pharmacokinetics of Paromomycin and Miltefosine Between Post-Kala-Azar Dermal Leishmaniasis and Visceral Leishmaniasis Patients in Eastern Africa

Treatment regimens for post-kala-azar dermal leishmaniasis (PKDL) are usually extrapolated from those for visceral leishmaniasis (VL), but drug pharmacokinetics (PK) can differ due to disease-specific variations in absorption, distribution, and elimination. This study characterized PK differences in paromomycin and miltefosine between 109 PKDL and 264 VL patients from Eastern Africa. VL patients showed 0.55-fold (95% confidence interval [CI], .41-.74) lower capacity for paromomycin saturable reabsorption in renal tubules, and required a 1.44-fold (95% CI, 1.23-1.71) adjustment when relating renal clearance to creatinine-based estimated glomerular filtration rate. Miltefosine bioavailability in VL patients was lowered by 69% (95% CI, 62%-76%) at treatment start. Comparing PKDL to VL patients on the same regimen, paromomycin plasma exposures were 0.74- to 0.87-fold, while miltefosine exposure until the end of treatment day was 1.4-fold. These pronounced PK differences between PKDL and VL patients in Eastern Africa highlight the challenges of directly extrapolating dosing regimens from one leishmaniasis presentation to another

Optimizing visceral leishmaniasis treatment in Eastern Africa: Understanding the pharmacokinetics and pharmacodynamics in a pediatric and malnourished population

Visceral leishmaniasis (VL) is a neglected tropical disease caused by the Leishmania parasite. There is a critical need for development of more effective and user-friendly treatment and diagnostics for this devastating and potentially fatal disease, especially in Eastern Africa, where treatment efficacy is suboptimal in this vulnerable and mainly pediatric population. To minimize the risks for either treatment failure or toxicity, VL drugs should be dosed precisely to reach the right drug exposure in the patient. To achieve this, pharmacokinetic studies are needed to describe the absorption, distribution, metabolism and elimination of VL drugs. In the first part of this thesis, the pharmacokinetics of paromomycin and miltefosine were studied, two favorable treatment options for VL. An optimized paromomycin-miltefosine combination regimen in Eastern African VL patients was developed, resulting in satisfactory cure rates and desired drug exposure levels in both pediatric and adult patients. Moreover, the impact of malnutrition and severity of disease on drug pharmacokinetics and exposure were studied and substantial and potentially clinically relevant effects of these factors were discovered. Secondly, the Leishmania parasite dynamics has been characterized in VL patients and the relationship between blood parasite load and relapse of disease, which is a long-term event that is difficult to predict. This thesis demonstrated that blood parasite load is a promising biomarker to predict relapse of disease already early after treatment. The knowledge gained in this thesis is a step forward to optimization, individualization and monitoring of VL treatment in Eastern Africa

Optimizing visceral leishmaniasis treatment in Eastern Africa

Visceral leishmaniasis (VL) is a neglected tropical disease caused by the Leishmania parasite. There is a critical need for development of more effective and user-friendly treatment and diagnostics for this devastating and potentially fatal disease, especially in Eastern Africa, where treatment efficacy is suboptimal in this vulnerable and mainly pediatric population. To minimize the risks for either treatment failure or toxicity, VL drugs should be dosed precisely to reach the right drug exposure in the patient. To achieve this, pharmacokinetic studies are needed to describe the absorption, distribution, metabolism and elimination of VL drugs. In the first part of this thesis, the pharmacokinetics of paromomycin and miltefosine were studied, two favorable treatment options for VL. An optimized paromomycin-miltefosine combination regimen in Eastern African VL patients was developed, resulting in satisfactory cure rates and desired drug exposure levels in both pediatric and adult patients. Moreover, the impact of malnutrition and severity of disease on drug pharmacokinetics and exposure were studied and substantial and potentially clinically relevant effects of these factors were discovered. Secondly, the Leishmania parasite dynamics has been characterized in VL patients and the relationship between blood parasite load and relapse of disease, which is a long-term event that is difficult to predict. This thesis demonstrated that blood parasite load is a promising biomarker to predict relapse of disease already early after treatment. The knowledge gained in this thesis is a step forward to optimization, individualization and monitoring of VL treatment in Eastern Africa.</jats:p

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

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.</p