A. Van Peer

The Clinical Pharmacokinetics of Itraconazole: An Overview

Summary: Itraconazole (R 51211) is the prototype of a class of triazole antifungals characterized by a high lipophilicity. This property determines to a large extent the pharmacokinetics of itraconazole and differentiates it from the hydrophilic triazole antifungal fluconazole.

The effects of food and dose on the oral systemic availability of itraconazole in healthy subjects

SummaryWe have studied the influence of food and dose (50, 100, 200 mg) on the oral systemic availability of the broad spectrum antifungal itraconazole and the pharmacokinetics after repeated dosing of 100 mg in six healthy volunteers.The relative systemic availability of itraconazole capsules compared with solution averaged 39.8% in the fasting state but 102% in the post-prandial state. Food did not significantly affect the tmax of the capsules. Itraconazole AUC at single doses of 50, 100, and 200 mg had a ratio of 0.3:1:2.7, and the steady-state AUC (0–24) after 15 days of 100 mg was five times the single-dose AUC.These findings suggest non-linear itraconazole pharmacokinetics in the range of therapeutically used doses. Furthermore, capsules should be given shortly after a meal to ensure optimal oral systemic availability.

Comparison of intravenous and intranasal sufentanil absorption and sedation

The absorption and sedation following an intranasal dose of sufentanil were evaluated and compared with those of the same dose given intravenously. Sixteen adult patients scheduled for elective surgery were randomly allocated to receive as premedication 15 μgsufentanil either intravenously or intranasally. Before administration and at fixed time intervals thereafter, the degree of sedation was assessed, vital signs were recorded and venous blood samples were taken for the determination of sufentanil plasma concentrations. Peroperative sedation of rapid onset and limited duration was seen in both groups. However, the onset of sedation was more rapid after intravenous injection. At 10 min, all patients in the TV group were sedated versus only two in the intranasal group (P < 0.01). No significant intergroup differences in sedation were seen at 20 to 60 min. This clinical effect is in agreement with the measured plasma levels, which were significantly lower after intranasal application at 5and 10 min, being 36 and 56 per cent of those after IV dosing, respectively. From 30 min, plasma concentrations were virtually identical for the two routes of administration. The AUCo-120 min after intranasal dosing was 78 per cent of that after intravenous injection. Intranasal dosing induced no clinically significant changes in vital signs, whereas after IV sufentanil, a clinically significant decrease in PaO2 was seen at 5 min. The results of this study show that sufentanil, when administered intranasally, is rapidly and effectively absorbed from the human nasal mucosa, so that this route may be an attractive alternative for a premedicant, avoiding the discomfort of an intravenous or intramuscular injection.RésuméNous avons comparé les voies intraveineuse et intranasale quant á l’absorption du sufentanil et á la sédation produite. Ainsi, en pré-opératoire d’ interventions électives, 16 adultes randomisés ont reccu 15 meg de sufentanil par voie veineuse ou nasale. Nous avons évalué l’effet sédatif, mesuré les signes vitaux et les niveaux sériques de sufentanil avant et á intervalle régulier aprés la prise du médicament. Un effet sédatif de courte durée est apparu rapidement avec le mode nasal alors que par mode vieneux, cemême effet survenait de façon encore plus pricoce. En fait, à dix minutes, il y avait sédation chez tous les patients du groupe veineux contre seulement deux patients du groupe nasal (P < 0,01) alors qu’á 20 et 60 minutes, les deux groupes étaient comparables. L’effet sédatifpeut être mis en paralléle avec les niveaux sériques de sufentanil qui á cinq et dix minutes post-instillation nasale n’atteignaient respectivement que 36 et 56 pour cent de ceux observé post-injection. A partir de 30 minutes, les niveaux sériques des deux groupes étaient pratiquement indentiques. Entre 0 et 120 minutes, l’aire sous la courbe des niveaux sériques (AUCo-120) atteints par voie nasale equivalait á 78 pour cent de celle produite par voie veineuse. Cinq minutes post-sufentanil IV, nous avons observé” une baisse significative de la PaO2 tandis que par voie nasale, les signes vitaux demeuraient inchangés. Ainsi, chez Vhumain, la muqueuse nasale absorbe rapidement le sufentanil et présente done une alternative á l’injection intraveineuse ou intramusculaire de la prém⩋ication.

Influence of age, renal and liver impairment on the pharmacokinetics of risperidone in man

The pharmacokinetics of the antipsychotic agent risperidone were investigated in healthy young and elderly subjects, cirrhotic patients and patients with moderate and severe renal insufficiency. In a comparative trial, a single oral 1-mg dose was administered to fasting subjects. Plasma and urine concentrations of the parent compound risperidone and the active moiety (i.e. risperidone plus 9-hydroxy-risperidone) were measured by radioimmunoassays. No or only small changes in plasma protein binding were observed in hepatic and renal disease, whereas the protein binding was not influenced by aging. The inter-individual variability in plasma concentrations of the active moiety was much less than the variability in plasma concentrations of risperidone. Three out of six subjects, behaving like poor metabolizers, were on medication (thiethylperazine, amitriptyline, metoprolol) that may inhibit risperidone metabolism by CYP2D6 (debrisoquine 4-hydroxylase). The pharmacokinetics of risperidone in elderly and cirrhotic patients were comparable to those in young subjects, whereas total oral clearance was reduced in renal disease patients. The elimination rate and clearance of 9-hydroxy-risperidone was reduced in elderly and renal disease patients because of a diminished creatinine clearance. The CLoral of the active moiety, which is primarily 9-hydroxy-risperidone, was reduced by about 30% in the elderly and by about 50% in renal disease patients. In addition, the t1/2 of the active moiety was prolonged (19 h in young subjects versus about 25 h in elderly and renal disease patients). Based upon the pharmacokinetics of the active moiety, a dose reduction and a cautious dose titration is advised in the elderly and in patients with renal disease. In cirrhotic patients, the single-dose pharmacokinetics were comparable to those in healthy young subjects.

New non-steroidal aromatase inhibitors: Focus on R76713

R76713 is a novel triazole derivative which selectively blocks the cytochrome P450-dependent aromatase. In human placental microsomes, in FSH-stimulated rat and human granulosa cells and in human adipose stromal cells, 50% inhibition of estradiol biosynthesis was obtained at drug concentrations of 2-10 nM. In PMSG-injected female rats, R76713 lowered plasma estradiol levels by 50 and 90% 2 h after single oral doses of 0.005 and 0.05 mg/kg respectively. After 1 mg/kg, estradiol levels were suppressed by 90% for 16 h. In male cynomolgus monkeys, R76713 dose-dependently (0.03-10 micrograms/kg) inhibited peripheral aromatization with an ED50 of 0.13 microgram/kg without altering metabolic clearance rates and conversion ratios. In vitro R76713 had no effect on other P450-dependent steroidogenic enzymes up to 1000 nM at least. In rats, LHRH-, ACTH- and sodium-deprived diet stimulated plasma testosterone, corticosterone and aldosterone levels were not modified 2 h after single oral administrations of R76713 (up to 20 mg/kg). Furthermore, R76713 did not show any in vitro or in vivo estrogenic or antiestrogenic property. R76713 also induced regression of DMBA-induced mammary tumors after daily oral administration of 1 mg/kg b.i.d. In male volunteers (n = 4), a single oral dose of 5 and 10 mg lowered median plasma estradiol levels from 70 pM to the detection limit of the assay (40 pM) 4, 8 and 24 h after intake whereas no changes were detected after placebo administration. In premenopausal women (n = 15), receiving a single oral dose of 20 mg, median plasma estradiol levels decreased from 389 pM (before) to 168, 133 and 147 pM, 4, 8 and 24 h after intake whereas they remained above 420 pM after placebo (n = 7).

Clinical Pharmacokinetics of Nebivolol

SummaryNebivolol is the racemic mixture of 2 isomers with 4 asymmetric centres. The d-isomer has the SRRR configuration, and the l-isomer is RSSS. Animal and human pharmacological experiments demonstrated that the antihypertensive and haemodynamic action of the racemic mixture was superior to that of the isomers alone. Many aspects affect the pharmacokinetics of the parent drug without making a firm impact on the clinical outcome. The absolute oral bioavailability of nebivolol varies from 12 to 96% in subjects characterised as extensive and poor debrisoquine hydroxylators. It is likely that active hydroxymetabolites compensate for the difference in both phenotype subjects. Active drug concentrations reflecting β-blockade by d-nebivolol and its hydroxymetabolites can be determined by a radioimmunoassay procedure using enantioselective antibodies. By the use of this method, comparable active drug concentrations were found in extensive and poor metabolisers, which explains why the clinical outcome is the same for both groups.

Pharmacokinetics of ketanserin and its metabolite ketanserin-ol in man after intravenous, intramuscular and oral administration

SummaryThe pharmacokinetics of ketanserin (R 41468), a novel serotonin S2-receptor blocking agent widely investigated for its effect on acute and chronic hypertension, has been studied in 10 healthy male subjects. They received single 10 mg doses i.v. and i.m., and 20, 40 and 60 mg solutions of ketanserin by mouth, in a five-way cross-over design. The model-independent kinetics of i.v. ketanserin were characterized by a terminal half-life of 14.3±4.4 h, a moderate plasma clearance (CL=565±57 ml/min) and a large tissue distribution (Vss=268±71 l, Vz=703±204 l; mean ± SD). Following i.m. administration, peak levels of nearly 200 ng/ml were attained within 10 minutes and the absolute bioavailability was 112±23%. After oral dosing, peak levels of ketanserin were reached within 1 h. The peak level and AUC increased in proportion to the dose. The absolute bioavailability was 46.8, 50.4 and 55.5% for 20, 40 and 60 mg doses and they conformed to the predicted bioavailability based on i.v. clearance data. The terminal half-life of 17 h and the urinary excretion of parent drug (about 0.7% of the dose) were similar after oral and parenteral dosing. The kinetics of ketanserin-ol, the major metabolite of ketanserin formed by ketone reduction, was also studied. Because of its negligible pharmacological activity, the contribution of ketanserin-ol to the overall therapeutic effect of ketanserin is small, in spite of its 1.6-times (parenteral) to 3.2-times (oral) higher plasma level than that of ketanserin. The particular role of the metabolite is discussed in the light of the clinical pharmacokinetics of ketanserin.

Pharmacokinetic approach to equilibrium between ketanserin and ketanserin-ol.

SummaryThe metabolic reduction-oxidation equilibrium between ketanserin and ketanserin-ol was studied after oral dosing of both substances to two healthy volunteers. Comparison of plasma Cmax and AUCs indicated that the equilibrium was shifted towards ketanserin-ol. There is evidence that ketanserin-ol elimination is the slowest step dictating the terminal half-life of ketanserin.

Alfentanil kinetics in renal insufficiency

SummaryAlfentanil 100 µg/kg was administered as an i.v. bolus to 9 patients with severe chronic renal dysfunction (creatinine clearance 1.0±1.2 ml/min) requiring regular haemodialysis. Plasma alfentanil concentrations were measured by a specific radioimmunoassay. Individual plasma concentration-time curves were fitted to a two-compartment open model. Mean distribution and elimination half-lives were 3.7 min and 58 min, respectively. The apparent volumes of distribution of the central compartment and the total volume of distribution at steady-state were 91 ml/kg and 304 ml/kg, respectively. Alfentanil plasma clearance was 5.3±2.5 ml/min/kg. All the patients tolerated alfentanil well and no side-effects nor delayed recovery were observed.

Pharmacokinetic-pharmacodynamic relationships in Phase I/Phase II of drug development

SummaryEarly investigation of pharmacokinetic-pharmacodynamic relationships in Phase I/II may facilitate the further clinical development of a new drug. Although some pharmacology assessments in Phase I are often only surrogates for the therapeutic effect, PK-PD modelling of those effects provides in general crucial information on the drug’s potency in vivo. A mathematical PK-PD expression allows explorative simulations on the rate of onset of drug action, on the intensity and duration of the effects for doses in future clinical trials, or in situations of altered drug kinetics. Furthermore, understanding of the PK-PD relationship early on in drug development may anticipate unnecessary exposure of human subjects to inappropriate drug doses or trials.