Population pharmacokinetics and prophylactic anti-emetic efficacy of ramosetron in surgical patients

Abstract

Aims: This study characterized the pharmacokinetics of ramosetron and compared prophylactic anti-emetic efficacy with that of ondansetron in a large population.

Methods: Fifty-eight patients consented to the pharmacokinetic analysis and were assigned randomly to receive 0.3, 0.45 or 0.6 mg ramosetron after induction of anaesthesia. Blood samples were acquired at preset intervals. Non-compartmental and population pharmacokinetic analyses were performed. In total, 1102 patients consented to the evaluation of prophylactic anti-emetic efficacy and were allocated randomly to receive 0.3 mg ramosetron or 4 mg ondansetron at the end of surgery. An additional 16 mg ondansetron were mixed in the intravenous patient-controlled analgesia pump of the ondansetron group. Post-operative nausea and vomiting (PONV) were evaluated 6, 24 and 48 h post-operatively using the Rhodes index of nausea, vomiting and retching (RINVR). Administration of rescue anti-emetics and adverse events were evaluated.

Results: The pharmacokinetic parameter estimates were V1 (l) = 5.12, V2 (l) = 108, CL (l⋅min(-1) ) = 0.08 + (59⋅age(-1) ) × 0.09, Q (l⋅min(-1) ) = 1.42. The incidences of PONV in the ramosetron and ondansetron groups were 77 (13.9%) and 113 (20.6%) and 44 (7.9%) and 66 (12.0%) at 24 and 48 h post-operatively, respectively (P = 0.004, 0.030). RINVR was significantly lower in the ramosetron than the ondansetron group 24 and 48 h post-operatively (P = 0.003, 0.025). Use of rescue anti-emetics and incidence of adverse events were comparable.

Conclusions: A two compartment mammillary model was used to describe ramosetron pharmacokinetics. Prophylactic anti-emetic efficacy of ramosetron was significantly better 24 and 48 h post-operatively than that of ondansetron, particularly when the Apfel score was ≥ 3.

Keywords: anti-emetics; pharmacokinetics; post-operative nausea and vomiting; ramosetron.

Figure 1

Goodness‐of‐fit plots for the final ramosetron pharmacokinetic model. A) Population predicted vs. measured plasma ramosetron concentrations and B) conditional weighted residuals (CWRES) vs. predicted plasma ramosetron concentration

Figure 2

Predictive checks of the final ramosetron pharmacokinetic model with A) 0.3, B) 0.45 and C) 0.6 mg ramosetron. Grey‐filled area represents the model's 95% prediction interval. Red solid line indicates the 50% prediction interval. +, measured plasma ramosetron concentration

Figure 3

Rhodes index of nausea, vomiting and retching (RINVR) scores for patients with A) an Apfel score of 1 (ramosetron/ondansetron: n = 76/81), B) an Apfel score of 2 (106/118), C) an Apfel score of 3 (308/294) or D) an Apfel score of 4 (67/60). Red solid lines indicate the median values, which were 0 for all. The RINVR ranges for patients with an Apfel score of 1 at 6, 24, and 48 h post‐operatively were 0–9/0–8, 0–15/0–14, and 0–5/0–4, respectively. For patients with an Apfel score of 2, 0–9/0–12, 0–12/0–10 and 0–6/0–6; for patients with an Apfel score of 3, 0–20/0–18, 0–15/0–32, and 0–12/0–17; for patients with an Apfel score of 4, 0–13/0–17, 0–10/0–24 and 0–16/0–20, respectively. *P < 0.05 vs. ondansetron according to the rank‐sum test. ramosetron, ondansetron