Christophe Gerbeau

Longitudinal assessment of everolimus in de novo renal transplant recipients over the first post‐transplant year: Pharmacokinetics, exposure‐response relationships, and influence on cyclosporine

Our objective was to characterize the steady‐state pharmacokinetics of everolimus and cyclosporine (INN, ciclosporin) when coadministered in de novo kidney allograft recipients during the first year after transplantation.

Population pharmacokinetics and exposure-response relationships for basiliximab in kidney transplantation

BACKGROUND Basiliximab is an interleukin-2 receptor (CD25) chimeric monoclonal antibody used for acute rejection prophylaxis in renal transplants. In the context of a randomized, double-blind efficacy trial, its population pharmacokinetics and potential exposure-response relationships were explored in de novo kidney allograft recipients receiving 40 mg basiliximab (20 mg on days 0 and 4) in addition to baseline immunosuppressive therapy with cyclosporine microemulsion and corticosteroids. METHODS Serial blood samples (8.2+/-1.3 per patient) were collected over 12 weeks after transplant from 169 basiliximab-treated patients, and empirical Bayes estimates of each patients disposition parameters were derived. The duration of CD25 saturation was estimated as the time over which serum basiliximab concentrations exceeded 0.2 microg/ml. The relationships between pharmacokinetic parameters and demographic-clinical covariates were explored by regression methods and unpaired t-tests. RESULTS Basiliximab clearance was 36.7+/-15.2 ml/hr, distribution volume 8.0+/-2.4 L, and half life 7.4+/-3.0 days. Patient weight (range, 44-131 kg) and age (range, 20-69 yrs) each contributed < or =6% to the variability in clearance and volume. Gender, ethnic group, and the presence of proteinuria had no clinically relevant influences on basiliximab disposition. Receptor-saturating basiliximab concentrations were maintained for 36+/-14 days (range, 12-91). There was no apparent relationship between the incidence or day of onset of acute rejection episodes during CD25 saturation and basiliximab concentration (range, 0.2-5.0 microg/ml). In patients who experienced a rejection episode after basiliximab was eliminated from serum (n=33), basiliximab had not been cleared faster than in their rejection-free peers (P=0.322) nor had CD25 been saturated for a shorter period of time (33+/-13 days vs. 37+/-14 days for rejection-free patients, P=0.162). CONCLUSIONS There were no demographic or clinical subpopulations not adequately treated with the standard basiliximab dosing regimen. Over the range of CD25 suppression durations observed in this study, extended periods of receptor blockade did not seem to confer an immunoprophylactic advantage compared with shorter periods of receptor suppression.

Longitudinal assessment of a P‐glycoprotein–mediated drug interaction of valspodar on digoxin

Valspodar is a P‐glycoprotein modulator currently under development as a multidrug resistance reversal agent in clinical oncology. A multiple‐dose drug interaction study was performed to assess the influence of valspodar on digoxin, a substrate for P‐glycoprotein.

Disposition and immunodynamics of basiliximab in liver allograft recipients

A randomized, open‐label prospective study was conducted with recipients of primary cadaveric liver allografts to characterize the disposition and immunodynamics of basiliximab, an interleukin‐2 receptor, α‐chain chimeric monoclonal antibody for immunoprophylaxis of acute rejection. Patients received a total intravenous dose of 40 mg basiliximab in addition to baseline dual immunosuppression consisting of cyclosporine (INN, ciclosporin) and steroids. The central distribution volume was 5.6 ± 1.7 L with a steady‐state volume of 7.5 ± 2.5 L. It was cleared slowly with a total body clearance of 75 ± 24 ml/hr and an elimination half‐life of 4.1 ± 2.1 days. Basiliximab was measurable in drained ascites fluid, and clearance by this route was an average of 20% of total clearance. Total body clearance correlated positively with volume of postoperative blood loss (r = 0.5253, p = 0.0101), suggesting that bleeding may represent an additional route of drug removal. A threshold relation was observed between serum concentration of basiliximab and CD25 expression on T lymphocytes whereby complete saturation of interleukin‐2 receptor α‐chain was maintained as long as serum concentrations exceeded 0.1 μg/ml. The duration of receptor saturation was 23 ± 7 days after transplantation (range, 13 to 41 days).

A rational dosing algorithm for basiliximab (Simulect) in pediatric renal transplantation based on pharmacokinetic-dynamic evaluations.

Background. The pharmacokinetics and immunodynamics of basiliximab were assessed in 39 pediatric de novo kidney allograft recipients to rationally chose a dose regimen for this age group. Methods. In study part 1, patients were given 12 mg/m2 of basiliximab by bolus intravenous injection before surgery and on day 4. An interim pharmacokinetic evaluation supported a fixed-dose approach for study part 2 in which infants and children received two 10-mg doses and adolescents received two 20-mg doses. Blood samples were collected over a 12-week period for analysis of basiliximab and soluble interleukin-2 receptor concentrations, flow cytometry, and screening for anti-idiotype antibodies. Results. Basiliximab clearance in infants and children (n=25) was reduced by approximately half compared with adults from a previous study and was independent of age (1–11 years), weight (9–37 kg), and body surface area (0.44–1.20 m2). Clearance in adolescents (12–16 years, n=14) approached or reached adult values. CD25-saturating basiliximab concentrations were maintained for 31±12 days in study part 1 with mg/m2 dosing and for 36±14 days in study part 2 based on the fixed-dose regimen (P =0.31). A single patient experienced a rejection episode during CD25 saturation. The duration of CD25 saturation in patients who experienced a rejection episode after desaturation did not differ from those who remained rejection-free for the full 6-month period: 34±6 days (n=6) vs. 35±14 days (n=33 patients);P =0.74. Anti-idiotype antibodies were detected in two patients; however, this did not influence the clearance of basiliximab or the duration of CD25 saturation. Conclusions. To achieve similar basiliximab exposure as is efficacious in adults, pediatric patients <35 kg should receive two 10-mg doses and those ≥35 kg should receive two 20-mg doses of basiliximab by intravenous infusion or bolus injection. The first dose is given before surgery and the second on day 4 after transplantation.

Differential influence of azathioprine and mycophenolate mofetil on the disposition of basiliximab in renal transplant patients

Pharmacokinetic sampling was performed in two multicenter trials in which basiliximab (anti‐CD25 monoclonal antibody) was administered with triple immunosuppression consisting of cyclosporine microemulsion, corticosteroids, and either azathioprine or mycophenolate mofetil. Blood samples were collected over 12 wk post‐transplant from 31 azathioprine‐treated and 66 mycophenolate mofetil‐treated patients. Empirical Bayes estimates of each patients basiliximab disposition parameters were derived and the duration of CD25 saturation was estimated as the time over which serum concentrations exceeded 0.2 μg/mL as confirmed by flow cytometry measurements. Basiliximab clearance was 29±14 mL/h when coadministered with azathioprine and 18±8 mL/h with mycophenolate mofetil. Both were significantly lower compared with a clearance of 37±15 mL/h from a previous study of basiliximab with dual therapy (p<0.001). As a consequence of the lower clearance of basiliximab, the durations of CD25 saturation were prolonged in the presence of azathioprine (50±20 d; range, 13–84) and mycophenolate mofetil (59±17 d; range, 28–94) compared with dual therapy (36±14 d; range, 12–91). A total of 27 acute rejection episodes occurred during the first 6 months in the two studies. Durations of CD25 saturation were not different in these patients compared with those who remained rejection‐free in each study. A single patient among 57 who were screened developed anti‐idiotype antibodies to basiliximab. The average duration of CD25 saturation was prolonged by 39 and 64% in the presence of azathioprine and mycophenolate mofetil, respectively. This graded effect was also observed for basiliximab clearance and may be due in part to a differentially reduced humoral response to basiliximab. Nonetheless, the range of CD25 saturation durations and basiliximab clearances did not extend outside the range when basiliximab was used with dual therapy in the absence of these agents. Hence, no dosing adjustment is deemed necessary when basiliximab is used in triple immunosuppressive therapy including either azathioprine or mycophenolate mofetil.

Screening for basiliximab exposure–response relationships in renal allotransplantation

The immunosuppressant basiliximab – a chimeric monoclonal antibody specific to the interleukin‐2 receptor on activated T‐lymphocytes – significantly reduces the incidence of acute cellular rejection following renal transplantation. Screening for exposure–response relationships was performed within a randomized, blinded, placebo‐controlled efficacy trial in which patients received 40 mg basiliximab (20 mg on days 0 and 4) by intravenous infusion in addition to cyclosporine and corticosteroids. In a subset of patients, serum samples were collected pre‐transplant and once in weeks 2, 3 and 4 for determination of basiliximab concentrations. A population pharmacostatistical model was used to derive individual empirical Bayes estimates of each patient’s pharmacokinetic parameters. Biopsy‐confirmed acute rejection episodes were recorded to month 6 post‐transplant. Forty basiliximab‐treated patients were evaluated, 30 men and 10 women, aged 48±12 yr (range, 24–73) and weighing 72.4±12.9 kg (range, 52.5–107.5). The basiliximab distribution volume was 7.5±1.7 L, the half‐life 7.5±2.5 d and the clearance 33±12 mL/h. There was no clinically relevant influence of weight, age, or gender on basiliximab disposition. Receptor‐saturating serum basiliximab concentrations (>0.2 μg/mL) were maintained for 41±23 d. Twenty‐five patients remained rejection‐free over the 6‐month observation period, while a total of 26 biopsy‐confirmed acute rejection episodes occurred in the remaining 14 patients. Of these episodes, 12 occurred during receptor blockade. No apparent relationship to basiliximab concentration on the day of onset was observed (range, 0.1–9.0 μg/mL) nor did the time of suppression offset represent a period of increased risk for rejection episodes. Fourteen rejection episodes occurred after basiliximab had cleared from the serum. The durations of receptor suppression preceding these events did not differ compared with those in patients who remained rejection‐free: 32±11 versus 45±26 d, respectively (p=0.1269). Given the durations of receptor saturation achieved with the chosen basiliximab regimen, this screen for exposure–response relationships did not identify the duration of receptor saturation in peripheral blood as a predictive factor for acute rejection episodes. Further exploration for exposure–effect relationships in a larger population is warranted.

Basiliximab in pediatric liver transplantation: A pharmacokinetic-derived dosing algorithm

Abstract: The pharmacokinetics and immunodynamics of basiliximab were assessed in 37 pediatric de novo liver allograft recipients to rationally design a dose regimen for this age‐group. In part one of the study, patients were given 12 mg/m2 basiliximab by bolus intravenous injection after organ perfusion and on day 4 after transplant. An interim pharmacokinetic evaluation supported a fixed‐dose approach for part two of the study in which infants and children received two 10‐mg doses of basiliximab and adolescents received two 20‐mg doses. Blood samples were collected over a 12‐week period for screening for anti‐idiotype antibodies and analysis of basiliximab and soluble interleukin‐2 receptor (IL‐2R) concentrations. Basiliximab clearance in infants and children < 9 yr of age (n = 30) was reduced by ≈ 50% compared with adults from a previous study and was independent of age to 9 yr, weight to 30 kg, and body surface area to 1.0 m2. Clearance in children and adolescents 9–14 yr of age (n = 7) approached or reached adult values. An average of 15% of the dose was eliminated via drained ascites fluid, and drug clearance via this route averaged 29% of total body clearance. Patients with > 5 L of ascites fluid drainage tended to have lower systemic exposure to basiliximab. CD25‐saturating basiliximab concentrations were maintained for 27 ± 9 days in part one of the study (mg/m2 dosing) with infants exhibiting the lowest durations. CD25 saturation lasted 37 ± 11 days in part two of the study, based on the fixed‐dose regimen (p = 0.004 vs. mg/mg2 dosing), but did not show the age‐related bias observed in part one of the study. Anti‐idiotype antibodies were detected in four patients, but this did not influence the clearance of basiliximab or duration of CD25 saturation. All 40 enrolled patients were included in the intent‐to‐treat clinical analysis. Episodes of acute rejection occurred in 22 patients (55%) during the first 12 months post‐transplant. Three patients experienced loss of their graft as a result of technical complications, and six patients died during the 12‐month study. Basiliximab was well tolerated by intravenous bolus injection, with no cytokine‐release syndrome or other infusion‐related adverse events. Hence, basiliximab was safe and well tolerated in pediatric patients undergoing orthotopic liver transplantation. To achieve similar basiliximab exposure as is efficacious in adults, pediatric patients < 35 kg in weight should receive two 10‐mg doses and those ≥ 35 kg should receive two 20‐mg doses of basiliximab by intravenous infusion or bolus injection. The first dose should be given within 6 h after organ perfusion and the second on day 4 after transplantation. A supplemental dose may be considered for patients with a large volume of drained ascites fluid relative to body size.

Constructing a prediction interval for time to reach a threshold concentration based on a population pharmacokinetic analysis: an application to basiliximab in renal transplantation.

Basiliximab is an immunosuppressant chimeric monoclonal antibody directed to the human interleukin-2 receptor α-chain used for prevention of acute rejection episodes in organ transplantation. The minimally effective serum concentration necessary to saturate receptor epitopes in kidney transplant patients is 0.2 μg/ml. To guide dose selection for Phase 3 efficacy trials, a population pharmacostatistical model was fitted to intensively sampled Phase 2 pharmacokinetic data. This served as a basis from which to examine candidate dose regimens with respect to the duration over which receptor-saturating concentrations would be achieved posttransplant. Three prediction methods were assessed: one based on simulations, and two others based on first-order approximation using either inverse regression or inversion of confidence intervals. An 80% prediction interval was generated by each method to evaluate its predictive performance against prospectively collected Phase 3 data in 39 renal transplant patients who received two injections of 20mg basiliximab, one prior to surgery and one on Day 4 posttransplant. All methods provided correct prediction of the duration of receptor-saturating concentration. As anticipated, the best performance was obtained from the simulation method which predicted 30 values in the 80% prediction interval, 19.7–52.7 days. The actually observed 80% interval from the Phase 3 data was 23.7–58.3 days.

Pharmacokinetics of Dexamethasone and Valspodar, a P‐glycoprotein (mdr1) Modulator: Implications for Coadministration

Study Objective. To assess the potential for a drug‐drug interaction between valspodar, a P‐glycoprotein (mdr1) modulator used as a chemotherapy adjunct, and dexamethasone, widely included in oncology antiemetic regimens.