Phase 1 Study of Maraviroc As Acute Graft-Versus-Host Disease Prophylaxis in Pediatrics

CCR5 is a chemokine receptor on activated effector T-cells, known to play a role in lymphocyte trafficking to the GI tract and liver. Maraviroc is an allosteric small molecule antagonist of CCR5 and has been used in adult allogeneic hematopoietic stem cell transplant (HSCT) recipients to prevent acute GVHD of the GI tract and liver but not skin GVHD. The dose of maraviroc and feasibility of oral administration in pediatric HSCT recipients is currently unknown. To establish feasibility, pharmacokinetic (PK) and pharmacodynamics (PD) profiles of maraviroc in pediatric HSCT recipients. Children ages 2-12 years were prospectively enrolled and maraviroc added to standard GVHD prophylaxis, which included a calcineurin inhibitor and steroids. Dosing of maraviroc (∼300 mg/m2) was based on limited pediatric HIV literature. Maraviroc was started on day-3 and administered orally twice daily until day+30 following stem cell infusion. On day zero and day+10, samples for PK analysis were collected pre-dose, and 1, 2, 4, 6, 8 and 12 hours after maraviroc administration. Additional trough concentrations were collected on day +7, 14 and 21 and samples analyzed by LC-MS/MS with a dynamic range of 1-1000ng/mL.PK parameters were analyzed by non-compartmental analysis. Target Cavg was >/= 100ng/mL. Patients were followed until day+100 for acute GVHD. To assess functional CCR5 blockade, whole blood from a healthy control (100μL) was incubated with 100μL of patient plasma obtained pre transplant, day 0 and day+14 for 30 minutes in the presence of 100nM CCL5 in 37°C and 5% CO2. Cells were stained with fluorescent antibodies against CD3, CD8, CD45RA, CCR7 and CCR5. Surface expression of CCR5 was calculated. Nine patients of median age 6 years (range 2-10 years) and underlying diagnoses of immune deficiency (n=4), hemoglobinopathy (n=4) and marrow failure (n=1) were enrolled. Bone marrow was the predominant stem cell source (n=8) compared to cord blood (n=1). Matched unrelated donors were predominant (n=5) compared to mismatched unrelated (n=3) and matched family donors (n=1). Mean ± SD AUCs were 3387±1563ng*h/mL on day 0 and 4750±1976 ng*h/mL on day+10 (Figures 1&2). All patients achieved target trough concentration by day+10. Two patients developed grade 1 acute skin GVHD prior to day+100 and were successfully treated with systemic corticosteroids. One patient developed grade 3 acute GI GVHD on day+24 after HSCT and had lower maraviroc exposure on day zero. Adherence to maraviroc by pharmacy and nursing documentation and parent reports was >95%. No adverse effects attributable to maraviroc were observed. All patients demonstrated functional CCR5 blockade on day zero (Figure 3). Administration of maraviroc is feasible in pediatric HSCT recipients with good safety and tolerability profile. These PK and PD data are being used to direct an ongoing phase II study.Figure 2Normalized maraviroc clearance.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure 3Pharmacodynamic assay showing functional blockade of CCR5 in patients enrolled on study. MVC= Maraviroc . CB= Control blood. When CCL5 binds to CCR5 on lymphocytes, it leads to CCR5 internalization and lack of CCR5 detection on surface flowcytometry. In healthy controls, it is expected to observe CCR5 internalization with addition of CCL5. This internalization does not occur when maraviroc is added to the sample, since it blocks CCR5 and prevents binding of CCL5. In patients on study, their pre BMT plasma was incubated with healthy control blood in the presence of CCL5 and CCR5 expression was not detected on flowcytometry due to expected internalization of CCR5. Day zero and day+14 plasma was incubated with healthy control blood in the presence of CCL5 (maraviroc starts on day - 3). No internalization of CCR5 was observed at day zero and day+14 since maraviroc in patients' plasma inhibited CCR5 on healthy control lymphocytes and prevented binding of CCL5 to CCR5.View Large Image Figure ViewerDownload Hi-res image Download (PPT)