Pharmacokinetics of piritramide in newborns, infants and young children in intensive care units

Piritramide is indicated for treatment of postoperative pain and analgosedation in the intensive care unit (ICU) setting. In an open prospective study the pharmacokinetics of piritramide were investigated in four groups: newborns (NB, age: 1–28 days) (n=8), infants 1 (IF1, age: 2–4 months) (n=7), infants 2 (IF2, age: 5–12 months) (n=14) and young children (YC, age: 2–4 years) (n=10). The recommended paediatric dose range for therapy of postoperative pain is 50–200 μg/kg. Piritramide was administered intravenously as a single dose by bolus injection of 50 μg/kg. Blood samples were collected at 0, 15, 45, 90 min and 3, 6, 9, 12 h after application, and urine samples were collected before application and during the following intervals: 1–2, 2–6, 6–12 h. Piritramide was measured in blood and urine by HPLC-ESI-MS. The following pharmacokinetic parameters: maximum plasma concentration (C_max), distribution half-life \({\left( {t_{{{\text{1}} \mathord{\left/ {\vphantom {{\text{1}} {2{\text{ $ \alpha $ }}}}} \right. \kern-\nulldelimiterspace} {2{\text{ $ \alpha $ }}}}} } \right)},\), elimination half-life\({\left( {t_{{{\text{1}} \mathord{\left/ {\vphantom {{\text{1}} {2{\text{ $ \beta $ }}}}} \right. \kern-\nulldelimiterspace} {2{\text{ $ \beta $ }}}}} } \right)},\), total clearance (Cl_t) and median volume of distribution at equilibrium (Vd_ss) were calculated using a non-compartment and a two-compartment model for the disposition of piritramide (TOPFIT and NONMEM-pharmacokinetic analysis). Newborns (NB) showed the highest maximum plasma concentrations (median±SD) C_max (79±240 μg/l) compared to the other three groups (IF1 36±367, IF2 12±81 and YC 16±9 μg/l) without statistical significance. The median elimination half-lives \({\left( {t_{{{\text{1}} \mathord{\left/ {\vphantom {{\text{1}} {{\text{2 $ \beta $ }}}}} \right. \kern-\nulldelimiterspace} {{\text{2 $ \beta $ }}}}} } \right)}\) were 702±720 min in NB, 157±102 min in IF1, 160±68 min in IF2 and 166±143 min in YC. For \(t_{{{\text{1}} \mathord{\left/ {\vphantom {{\text{1}} {{\text{2 $ \beta $ }}}}} \right. \kern-\nulldelimiterspace} {{\text{2 $ \beta $ }}}}} \) the difference between NB and the other three groups (IF1, IF2 and YC) was statistically significant (Mann-Whitney-U, P<0.05). Cl_t was 15.9±16.7, 46.6±76.9, 235.5±454.1 and 338±168.1 ml/min in NB, IF1, IF2 and YC respectively. The total clearance increased exponentially with an elimination half-life of 702 min from 15.9 ml/min in NB to 46.6 ml/min in IF2. Differences between the NB/IF1 groups and IF2/YC groups were significantly significant (NB vs. IF2, NB vs. YC, IF1 vs. IF2 and IF1 vs. YC). Vd_ss was 2.0±4.93, 1.7±2.5, 7.0±5.2 and 6.7±2.2 l/kg in NB, IF1, IF2 and YC respectively. In comparison to group IF1 the Vd_ss was significantly larger in groups IF2 and YC (Mann-Whitney U, P<0.05). Newborns showed a high initial concentration and a distinct prolongation of the elimination half-life of piritramide compared to infants, young children and adults. Therefore, dosage needed to treat postoperative pain should be reduced, and the repetitive doses should be geared to the analgesic effects. In infants and young children the elimination of piritramide is increased compared to adults; therefore the duration of the effects of piritramide will be shortened, and dose intervals ought to be reduced. Subsequent clinical trials for detailed dose adjustment of piritramide in paediatric patients comparing pharmacokinetics and effectiveness are needed.