Prolactin release after remoxipride by an integrated pharmacokinetic-pharmacodynamic model with intra- and interindividual aspects.

An integrated pharmacokinetic-pharmacodynamic model is suggested for remoxipride and its effect on prolactin (PRL) release acting by preventing the inhibitory effect of dopamine D2 receptors in the anterior pituitary. The model was implemented to describe the time course of PRL plasma levels after administration of two consecutive doses of remoxipride at 5 different time intervals, 2, 8, 12, 24 and 48 hr. The model used is an indirect response model. It consists of three parts: 1) the pharmacokinetics of remoxipride; 2) a physiological substance model for PRL, incorporating the synthesis of PRL and its release into and elimination from plasma; and 3) a pharmacodynamic model describing the influence of remoxipride on the PRL release from the pool. A linear pharmacodynamic model gave the best description of the time course of PRL. The limitation in the PRL release is the amount available in the pool, which takes 24 to 48 hr to fully restore, rather than a maximal effect of remoxipride. The intra- and interindividual variability of remoxipride as well as of the PRL response was low.

An open study of tolerability and pharmacokinetics of raclopride extended release capsules in psychiatric patients: a Canadian study.

The tolerability and pharmacokinetics of raclopride extended release (ER) capsules have been evaluated after a single oral dose and at steady state, with 3 different daily doses in 4 male patients requiring neuroleptic treatment. In this 3-week open study, the drug was administered to patients in increasing bid doses of 8 mg, 12 mg and 16 mg, respectively, for each 1-week treatment period, following a 1-week placebo washout. With this limited number of patients, assessments of clinical chemistry, hematology, cardiovascular variables and adverse symptoms suggest that raclopride is safe and well-tolerated in the group studied. The administration of repeated doses of raclopride showed linear pharmacokinetics based on parameter values which are either constant (effective elimination half-life, total plasma clearance, and dose-normalized area under the plasma concentration-time curve) or varying proportionally (trough plasma concentration, peak plasma concentration, average plasma concentration and the area under the plasma concentration-time curve for a dosage interval at steady state) with the doses. The linear 1-compartment open model with zero-order absorption was the most appropriate pharmacokinetic model describing the raclopride plasma concentration profile after a single 8 mg dose of raclopride ER capsules. The ER formulation reduced the fluctuation between peak and trough plasma drug concentrations which has been reported before with instant release dosage forms. In this study, the increase of plasma prolactin concentrations above the normal limit was transient and returned to normal levels. Although the plasma prolactin concentration tended to increase with the drug dose, no direct relationship between raclopride dose and prolactin plasma concentrations was found. The correlation of plasma prolactin response with the plasma raclopride concentration showed a low level of hysteresis.

Influence of the dosing interval on prolactin release after remoxipride.

1. The prolactin response following administration of the D2-dopamine receptor antagonist remoxipride was studied in eight healthy male volunteers. The purpose of the study was to investigate the duration of a refractory period of prolactin release following two doses of remoxipride. A further aim was to compare the prolactin response following remoxipride and thyrotropin release hormone (TRH) during the refractory period. The subjects received two 30 min intravenous (i.v.) infusions of remoxipride 50 mg with different time intervals between the two doses, in a randomized six period crossover design. The time intervals between the two remoxipride doses were 2, 8, 12, 24 and 48 h. On one occasion the remoxipride dose was followed by an i.v. injection of TRH after 2 h. 2. The plasma peak prolactin concentrations obtained after the first remoxipride dose correspond to a maximal release of prolactin according to earlier studies. A small second peak of prolactin was observed after 2 h. The release was gradually increased with longer time intervals between the consecutive doses. The refractory period for a second prolactin release similar to the first one after remoxipride was found to be 24 h for most of the subjects. 3. TRH resulted in a faster and higher increase in prolactin response of a shorter duration than after remoxipride administered 2 h after the first dose.

Influence of rate of administration of raclopride on akathisia and prolactin response.

The D2-dopamine receptor antagonist raclopride was administered to eight healthy male subjects, who had previously experienced akathisia following antipsychotic drugs. The influence of administration rate on onset, severity and duration of akathisia and on prolactin response was studied. Raclopride 3, 5 or 9 mg or placebo (P) was administered as single IV infusions during 10 min (R10 min/3 mg), 1 h (R1h/5 mg) or 4 h (R4h/9 mg) according to a randomized double-blind design. Despite a 24-fold difference in administration rate a similar peak raclopride concentration of about 350 nmol/l was obtained after all three infusions. Three of the eight subjects experienced akathisia following R10 min/3 mg and R1h/5 mg, respectively. After R4h/9 mg seven subjects experienced akathisia of longer duration but not more severe than after the short infusions. The incidence and duration of akathisia seem to be mainly related to the plasma raclopride concentrations over time, whereas the rate of administration might be more important for the severity. A maximal prolactin response was induced which was not markedly affected by the rate of administration.

The pharmacokinetics of remoxipride and metabolites in patients with various degrees of renal function.

1. The pharmacokinetics of remoxipride, a new neuroleptic, were investigated in an open study with three parallel groups. Twenty-one patients with severely impaired (ClCr < 25 ml min-1), moderately impaired (ClCr 25-50 ml min-1) and normal (ClCr > 65 ml min-1) renal function were evaluated. A single oral dose of remoxipride hydrochloride 100 mg was administered, and blood and urine were collected over 48 h. Concentrations of remoxipride and metabolites were measured by h.p.l.c. 2. In patients with severely decreased renal function, the AUC and Cmax of remoxipride were increased significantly, and t1/2 was prolonged, as compared with the control patients. The renal clearance and urinary recovery of the unchanged drug were significantly diminished. 3. The unbound fraction of remoxipride in plasma was decreased in patients with renal failure, in association with a disease-related increase in alpha 1-acid glycoprotein. In spite of a 25% recovery of unchanged drug in the urine in patients with normal renal function, the AUC of unbound drug was twice as high in patients with severely impaired renal function. 4. A strong correlation between creatinine clearance and renal drug clearance was observed indicating a direct relationship between kidney function and the renal clearance of remoxipride. 5. Remoxipride was the predominant compound in plasma as well as in urine in patients with severely decreased as well as normal renal function. In patients with severely decrease renal function, remoxipride and all five pharmacologically inactive metabolites showed increased peak plasma concentrations, delayed tmax, increased AUC, prolonged half-lives and decreased renal clearance.

An open study of the pharmacokinetics and the tolerability of raclopride extended release capsules in psychiatric patients.

Following a 4-7 day drug-free washout period, eight male inpatients took an extended-release (ER) formulation of raclopride. After the initial 8 mg dose on day 1 of the study, repeated plasma samples were collected over the ensuing 36 h. Subsequently, patients received raclopride 8 mg b.i.d. through day 7, 12 mg b.i.d. through day 14, and, if tolerated, 16 mg b.i.d. through day 21. On days 7, 14, and 21, repeated plasma samples were drawn over the 12 h following the morning dose. Relative to the previously studied immediate release form of raclopride, the ER formulation delayed and extended the absorption of raclopride, and produced lower maximum raclopride concentrations. Linear kinetics were preserved across the dose range studied. Two patients could not tolerate the highest raclopride dose because of extrapyramidal side effects.

Pharmacokinetics of raclopride formulations. Influence of prolactin and tolerability in healthy male volunteers.

The pharmacokinetic and pharmacodynamic properties of raclopride, a new antipsychotic, were investigated in 16 healthy men. Single 4 mg doses were administered as intravenous infusion, oral solution and 2 extended release (ER) formulations. Total plasma clearance was about 100 ml/min (6.0 L/h), of which renal clearance accounted for 0.2 ml/min, indicating extensive metabolism. The volume of distribution was 1.5 L/kg; mean absolute bioavailability was 65 to 67% following the oral solution and the ER formulations. A transient increase in plasma prolactin levels followed both the intravenous infusion and the oral solution. The ER formulations resulted in a lower increase, which appeared later. However, the area under the prolactin level curve was similar after administration of all dosage forms. The frequency and severity of the most commonly reported side effects (tiredness and restlessness) were higher after the intravenous infusion than after the ER capsules. These findings indicate that such capsules may be advantageous for clinical antipsychotic treatment with raclopride.

Remoxipride: pharmacokinetics and effect on plasma prolactin.

1. The pharmacokinetics of remoxipride, a new neuroleptic, were investigated in 15 healthy subjects after an intravenous infusion of 50 mg, an intramuscular injection of 100 mg and after administration of two immediate release capsules (A and B), each of 100 mg, in a cross-over study. The effect of the different remoxipride formulations on plasma prolactin concentrations was also studied. 2. The volume of distribution of remoxipride was 0.65 +/- 0.11 kg-1 (mean +/- s.d.). Total plasma clearance was 119 +/- 39 ml min-1, of which 31 +/- 13 ml min-1 was due to renal clearance. The absolute bioavailability after the i.m. and oral formulations was greater than 90%, indicating a small extent of first-pass metabolism. The mean elimination half-life was 4.8 +/- 1.4 h. The unbound fraction of remoxipride and the blood/plasma ratio were 0.19 +/- 0.03 and 0.64 +/- 0.06, respectively. 3. The transient increase in plasma prolactin was similar after all four remoxipride administrations and independent of the given dose.