Robert Woestenborghs - Academia.edu (original) (raw)
Papers by Robert Woestenborghs
Journal of Chromatography B: Biomedical Sciences and Applications, 1983
Survey of Anesthesiology, 1996
The cerebrospinal fluid (CSF) and plasma pharmacokinetics of sufentanil were studied in 29 adult ... more The cerebrospinal fluid (CSF) and plasma pharmacokinetics of sufentanil were studied in 29 adult patients undergoing thoracotomy under general anesthesia. Sufentanil, 75 micrograms, diluted in 10 mL saline, was given preoperatively in either the lumbar or thoracic epidural space to 14 and 15 patients, respectively. Lumbar CSF and plasma were frequently sampled for 10 h and analyzed for sufentanil concentration by radioimmunoassay. In plasma, the area under the concentration curve (AUC) did not differ between the groups. The fraction of the lumbar epidural dose found in CSF was calculated to be 2.7%. The time to peak CSF sufentanil concentration differed (P < 0.01) after epidural administration in the lumbar (0.76 +/- 0.50 h) and thoracic (2.1 +/- 1.4 h) region. In the lumbar group, the AUC and Cmax values in CSF were 19 (P < 0.01) and 45 (P < 0.01) times higher than in plasma, and 4.7 (P < 0.01) and 8.2 (P < 0.001) times higher than in CSF in the thoracic group. The decline in sufentanil concentration was more rapid in CSF than plasma; in the lumbar group the CSF/plasma concentration-ratio was eight and five at 6 and 10 h, respectively, after sufentanil administration. This study shows that after epidural administration sufentanil concentrations are higher in CSF than in plasma, and are highly localized within CSF to the site of administration.
Bioanalysis of Drugs and Metabolites, Especially Anti-Inflammatory and Cardiovascular, 1988
Clinical Pharmacokinetics, 1995
The linear and predictable pharmacokinetic properties of the histamine H1-receptor antagonist lev... more The linear and predictable pharmacokinetic properties of the histamine H1-receptor antagonist levocabastine make it particularly suitable for intranasal or ocular treatment of allergic rhinoconjunctivitis. Peak plasma concentrations (Cmax) occur within 1 to 2 hours of administration of single doses of levocabastine nasal spray and eye drops (0.2mg and 0.04mg, respectively). Drug absorption is incomplete after intranasal and ocular administration, with systemic availability ranging from 60 to 80% for levocabastine nasal spray and from 30 to 60% for the eye drops. However, as the amount of levocabastine applied intranasally and ocularly is small, the levocabastine plasma concentrations achieved are extremely low, with Cmax values in the ranges 1.4 to 2.2 micrograms/L and 0.26 to 0.29 micrograms/L for intranasal and ocular administration, respectively. Pharmacokinetic-pharmacodynamic modelling has indicated that the clinical benefits of levocabastine are predominantly mediated through local antihistaminic effects, although some systemic activity may contribute to the therapeutic efficacy of levocabastine nasal spray during long term use. Levocabastine undergoes minimal hepatic metabolism, i.e. ester glucuronidation, and is predominantly cleared by the kidneys. Approximately 70% of parent drug is recovered unchanged in the urine. Plasma protein binding is approximately 55% and the potential for drug interactions involving binding site displacement is negligible. Furthermore, the pharmacokinetics of this agent do not appear to be influenced by either age or gender. Levocabastine nasal spray and eye drops may thus be considered suitable for the treatment of allergic rhinoconjunctivitis in a wide patient population.
Bioanalysis of Drugs and Metabolites, Especially Anti-Inflammatory and Cardiovascular, 1988
Journal of chromatography, Jan 11, 1979
A method is described for the determination of the antiarrhythmic drug lorcainide hydrochloride a... more A method is described for the determination of the antiarrhythmic drug lorcainide hydrochloride and its three main metabolites in plasma, urine, faeces and tissues from man and animals. The procedure involves the extract of the parent drug, its metabolites and the internal standard from the biological materials at different alkaline pH values, back-extraction into sulphuric acid and re-extraction into the organic phase (heptane--isoamyl alcohol). After silylation of the different phenolic and the N-dealkylated metabolites, analyses were carried out by automated gas--liquid chromatography with electron-capture detection. The method has a sensitivity limit of 5 ng for lorcainide, and 10--20 ng for the various metabolites, per millilitre of plasma. The method was applied to urine, faeces, plasma and tissue samples from man and animals. It was also suitable for automatic sample analysis.
Journal of Chromatography B, 2003
A high-pressure liquid chromatography with ultra-violet detection method for the simultaneous det... more A high-pressure liquid chromatography with ultra-violet detection method for the simultaneous determination of risperidone and 9-hydroxyrisperidone in plasma after liquid-liquid extraction has been developed. The limit of quantitation was 5 nmol / L, and the inter-day coefficient of variation was less than 8% for both compounds. The mean recoveries of risperidone and 9-hydroxyrisperidone added to plasma were 96.8 and 99.4%, with an intra-day coefficient of variation of under 5 and 6%, respectively. Studies of analytical interference showed that the most commonly co-administered antidepressants and benzodiazepines did not interfere. The method was used for the determination of the plasma concentrations of a schizophrenic patient treated daily with an oral dose of 4.5 mg risperidone. The patient suffered severe extrapyramidal side-effects after adding risperidone to his previous medication of haloperidol and levomepromazine. The risperidone plasma concentration was well above the average (182 nmol / L), which suggests that a pharmacokinetic interaction occurred, presumably due to inhibition of the enzyme CYP2D6.
Clinical Cancer Research, 2000
This Phase I study was performed to assess the feasibility of combining docetaxel with the new P-... more This Phase I study was performed to assess the feasibility of combining docetaxel with the new P-glycoprotein inhibitor R101933 and to determine the dose limiting toxicity of this combination. Fifteen patients received oral R101933 alone at a dose escalated from 200 to 300 mg twice daily (b.i.d.; cycle 0), an escalating i.v. dose of docetaxel (60, 75, and 100 mg/m 2 ) as a 1-h infusion (cycle 1), and the combination (cycle 2 and further). Dose limiting toxicity consisting of mucositis and neutropenic fever was reached at the combination of docetaxel, 100 mg/m 2 , and R101933, 300 mg b.i.d., and the maximum tolerated dose was established at docetaxel, 100 mg/m 2 , and R101933, 200 mg b.i.d. Plasma concentrations of R101933 achieved in patients were in the same range as required in preclinical rodent models to overcome paclitaxel resistance. The plasma pharmacokinetics of docetaxel were not influenced by the R101933 regimen at any dose level tested, as indicated by plasma clearance values of 26.5 ؎ 7.78 liters/h/m 2 and 23.4 ؎ 4.52 liters/h/m 2 (P ؍ 0.15) in cycles 1 and 2, respectively. These findings indicate that the contribution of a P-glycoprotein inhibitor to the activity of anticancer chemotherapy can now be assessed in patients for the first time independent of its effect on drug pharmacokinetics.
Ketoconazole is an orally effective, broad-spectrum, systemic antifungal agent. The pharmacokinet... more Ketoconazole is an orally effective, broad-spectrum, systemic antifungal agent. The pharmacokinetics and bioavailability of ketoconazole given as a 200-mg single dose in a tablet, suspension, or solution were studied in 24 fasting healthy males by using a crossover design. Levels of ketoconazole in plasma were determined for up to 48 h by a sensitive reverse-phase high-performance liquid chromatography method. The absorption of ketoconazole was rapid, with mean maximum concentrations of the drug in plasma of 4.2, 5.0, and 6.2 ,g/ml attained at 1.7, 1.2, and 1.0 h, respectively, after administration of the tablet, suspension, and solution, respectively. The mean distribution and elimination half-life values were 1.5 to 1.7 and 7.5 to 7.9 h, respectively. The mean oral clearance of the solution dose was 209 (+82.9 [standard deviation]) ml/min, and the mean apparent volume of distribution was 88.31 (±68.72) liters. The relative bioavailabilities for the tablet and suspension were 81.2 (±33.5) and 89.0 (±23.1)%, respectively, of that of the solution. The data indicated the bioequivalence of the tablet to the suspension and of the suspension to the solution. Dose proportionality of ketoconazole was also studied in 12 volunteers after they received solution doses of 200, 400, and 800 mg. Linear correlations between the dose and the maximum concentration of the drug in plasma, the time to the maximum concentration, and the area under the concentration-time curve were observed. However, the increase in the area under the curve was more than proportional to the dose given. The levels in plasma seemed to decay at a lower rate after 400and 800-mg doses. The mean oral clearance decreased from 244.9 to 123.6 and 80.0 ml/min, respectively, as the dose increased from 200 to 400 and 800 mg. The apparent dose-dependent kinetics may have been due to the presystemic elimination and capacity-limited hepatic metabolism which become saturated at higher doses.
Clinical cancer research : an official journal of the American Association for Cancer Research, 2000
This Phase I study was performed to assess the feasibility of combining docetaxel with the new P-... more This Phase I study was performed to assess the feasibility of combining docetaxel with the new P-glycoprotein inhibitor R101933 and to determine the dose limiting toxicity of this combination. Fifteen patients received oral R101933 alone at a dose escalated from 200 to 300 mg twice daily (b.i.d.; cycle 0), an escalating i.v. dose of docetaxel (60, 75, and 100 mg/m2) as a 1-h infusion (cycle 1), and the combination (cycle 2 and further). Dose limiting toxicity consisting of mucositis and neutropenic fever was reached at the combination of docetaxel, 100 mg/m2, and R101933, 300 mg b.i.d., and the maximum tolerated dose was established at docetaxel, 100 mg/m2, and R101933, 200 mg b.i.d. Plasma concentrations of R101933 achieved in patients were in the same range as required in preclinical rodent models to overcome paclitaxel resistance. The plasma pharmacokinetics of docetaxel were not influenced by the R101933 regimen at any dose level tested, as indicated by plasma clearance values o...
Pharmacotherapy
The bioavailability of risperidone was evaluated in an open-label, randomized, two-way, crossover... more The bioavailability of risperidone was evaluated in an open-label, randomized, two-way, crossover study comparing a 1-mg tablet with a 1-mg/ml oral solution. Both formulations were administered as a single 1-mg dose with a 10-day washout period between treatments. Of 26 healthy men who entered the study, 23 completed both treatment periods. Plasma concentrations of risperidone and the active moiety (risperidone plus its active metabolite, 9-hydroxyrisperidone) were determined by radioimmunoassays. For key pharmacokinetic values (Cmax, AUC), the 90% CIs on the relative bioequivalence of risperidone, 9-hydroxyrisperidone, and the active moiety were contained within the equivalence range of 80-120% (80-125% for log-transformed data). The results demonstrate that the 1-mg/ml oral solution and the 1-mg tablet are bioequivalent.
Clinical Pharmacology and Therapeutics, 1984
Alfentanil disposition after an intravenous bolus of 50 pglkg was followed in 15 elderly surgical... more Alfentanil disposition after an intravenous bolus of 50 pglkg was followed in 15 elderly surgical patients and was compared to that in nine young adults. A two-compartment open model described alfentanil disappearance from plasma. Apparent volumes of distribution of the central compartment (201 and 211 ml/kg; k), at steady state (460 and 543 ml/kg), and of the AUC (746 and 722 ml/kg) in young adults and in elderly subjects did not differ. Plasma clearance was lower in elderly subjects (4.4 ml/mm/kg) than in young adults (6.5 ml/mm/kg), whereas terminal plasma t1/2 was longer in the elderly patients (137 and 83 min). Alfentanil dosage should therefore be reduced in elderly patients when large single doses, multiple doses, or long-term infusions are required.
Pharmacy World amp; Science, 1993
Pharmaceutisch Weekblad, 1987
Pediatric Hematology-Oncology, 1989
Two consecutive nonrandomized studies were conducted in children with prolonged granulocytopenia ... more Two consecutive nonrandomized studies were conducted in children with prolonged granulocytopenia to evaluate the prophylactic antifungal activity of ketoconazole and the new triazole itraconazole. The conditions were equivalent in both studies. The incidence of colonization was 10% in the ketoconazole group and 19% in the itraconazole group (this difference is not significant). For suspected and proven infections, the incidence was 5% for ketoconazole and 10% for itraconazole, but the incidences were too low for statistical comparison. Although the colonization rate was higher for itraconazole, there was no sign of Aspergillus, whereas in the ketoconazole group an autopsy, proven aspergillosis has been reported.
Journal of Veterinary Pharmacology and Therapeutics, 1988
with R 81 101 fentanyl in the dog: pharmacodynamic and pharmacokinetic interactions. J . vet. Pha... more with R 81 101 fentanyl in the dog: pharmacodynamic and pharmacokinetic interactions. J . vet. Pharmacol. Therap. 11, 63-70. The pharmacokinetics and clinical effects of the short-acting hypnotic R 81 10 and of the narcotic analgesic fentanyl were studied in the dog. T h e effects of separate intravenous (i.v.) injections of R 81 10 (4 mg/kg) and fentanyl(O.015 mg/kg) and of concurrent i.v. injection of the two were studied. After administration of R 81 10, induction of hypnosis occurred within 1 min, maximal depth of anaesthesia and satisfactory analgesia and muscle relaxation were obtained after 5 min. The effects had decreased within 15 min and full recovery occurred within 30 min. Fentanyl alone produced neither hypnosis nor muscle relaxation. When fentanyl and R 81 10 were given simultaneously, the duration of hypnosis was doubled in comparison with R 81 10 alone. Moreover, markedly improved and longer lasting analgesia and muscle relaxation were observed with the combination. When the drugs were injected together, the plasma concentrations of R 8110 were initially much higher than after separate injection of R 8110, but they became similar after 30 min. Although statistically non-significant, fentanyl reduced the total plasma clearance of R 81 10 (31.1 f 6.9 vs. 21.9 k 2.3 mVkg/min) and decreased the volume of distribution (3.78 k 1.83 vs. 2.23 k 0.90 Vkg, P < 0.05). Fentanyl did not alter the elimination half-life of R 81 10. R 81 10 had no apparent influence on the pharmacokinetics of fentanyl.
Biological Mass Spectrometry, 1989
The Journal of Clinical Pharmacology, 1993
The effects of renal insufficiency and hemodialysis on the pharmacokinetics of orally administere... more The effects of renal insufficiency and hemodialysis on the pharmacokinetics of orally administered levocabastine were studied in six nondialysis patients and in six patients undergoing regular hemodialysis. Levocabastine .5 mg, supplied as a solution, was administered orally to each patient 1 hour after breakfast. Compared with data in healthy volunteers, the oral absorption and disposition of levocabastine were impaired in patients with renal insufficiency. The time to reach peak plasma concentration was increased and the peak plasma concentration was decreased in the patients with renal insufficiency compared with healthy volunteers. Urinary excretion of the unchanged drug, which is the major elimination pathway of levocabastine, was reduced in the patients with renal insufficiency. The decreased urinary excretion most likely contributed to the prolonged half-life (from 36 hours to 95 hours) and increased area under the plasma concentration-time curve (+56%) in the patients with renal insufficiency as compared with the healthy volunteers. Although the 6-hour hemodialysis procedure starting 4 hours after dosing eliminated 10% of the oral dose, the terminal half-life and the total area under the plasma concentration-time curve did not differ significantly between the hemodialysis and the nonhemodialysis patients. In conclusion, the current study showed that the initial oral absorption of levocabastine is reduced and that levocabastine elimination is prolonged in patients with renal insufficiency.
The Journal of Clinical Pharmacology, 1998
A randomized, open-label, comparative study was conducted in 30 male patients with moderately adv... more A randomized, open-label, comparative study was conducted in 30 male patients with moderately advanced human immunodeficiency virus (HIV) infection to examine the pharmacokinetics of an investigational intravenous preparation of itraconazole compared with pharmacokinetics after administration of itraconazole capsules. The study also assessed whether adequate plasma concentrations of itraconazole could be rapidly achieved with the intravenous formulation and then maintained after cessation of intravenous therapy with itraconazole capsules. All patients received 200 mg intravenous itraconazole as a 1-hour infusion in 40% hydroxypropyl-beta-cyclodextrin (HP-beta-CD) vehicle twice daily for 2 days, and then 200 mg intravenously once daily for 5 days. Patients then received itraconazole capsules, either 200 mg twice daily or 200 mg once daily for 28 days. Steady-state plasma concentrations of itraconazole were reached by day 3 with intravenous infusion, a much shorter time than observed with administration of itraconazole capsules. Steady-state concentrations of itraconazole and hydroxyitraconazole were effectively maintained during the rest of the intravenous infusions of itraconazole. Oral follow-up with administration of 200-mg capsules once daily could not maintain the plasma concentrations of itraconazole and hydroxyitraconazole obtained at the end of the intravenous treatment, whereas twice-daily oral administration maintained or increased these concentrations. Mean plasma concentrations of itraconazole and hydroxyitraconazole on day 7 were similar to those on day 36 in the twice-daily group. Mean renal clearance was comparable to mean total body clearance, and approximately 93% to 101% of the HP-beta-CD was excreted unchanged in urine within 12 hours of administration. The HP-beta-CD was essentially eliminated through the kidney, and little accumulation in the body was observed in this patient population. Adverse events during the intravenous phase were most commonly associated with intravenous administration. Intravenous infusion of itraconazole for 7 days followed by administration of itraconazole capsules twice daily for 28 days is an effective dose regimen in patients with advanced HIV infection.
Pharmacy World & Science, 1983
Journal of Chromatography B: Biomedical Sciences and Applications, 1983
Survey of Anesthesiology, 1996
The cerebrospinal fluid (CSF) and plasma pharmacokinetics of sufentanil were studied in 29 adult ... more The cerebrospinal fluid (CSF) and plasma pharmacokinetics of sufentanil were studied in 29 adult patients undergoing thoracotomy under general anesthesia. Sufentanil, 75 micrograms, diluted in 10 mL saline, was given preoperatively in either the lumbar or thoracic epidural space to 14 and 15 patients, respectively. Lumbar CSF and plasma were frequently sampled for 10 h and analyzed for sufentanil concentration by radioimmunoassay. In plasma, the area under the concentration curve (AUC) did not differ between the groups. The fraction of the lumbar epidural dose found in CSF was calculated to be 2.7%. The time to peak CSF sufentanil concentration differed (P < 0.01) after epidural administration in the lumbar (0.76 +/- 0.50 h) and thoracic (2.1 +/- 1.4 h) region. In the lumbar group, the AUC and Cmax values in CSF were 19 (P < 0.01) and 45 (P < 0.01) times higher than in plasma, and 4.7 (P < 0.01) and 8.2 (P < 0.001) times higher than in CSF in the thoracic group. The decline in sufentanil concentration was more rapid in CSF than plasma; in the lumbar group the CSF/plasma concentration-ratio was eight and five at 6 and 10 h, respectively, after sufentanil administration. This study shows that after epidural administration sufentanil concentrations are higher in CSF than in plasma, and are highly localized within CSF to the site of administration.
Bioanalysis of Drugs and Metabolites, Especially Anti-Inflammatory and Cardiovascular, 1988
Clinical Pharmacokinetics, 1995
The linear and predictable pharmacokinetic properties of the histamine H1-receptor antagonist lev... more The linear and predictable pharmacokinetic properties of the histamine H1-receptor antagonist levocabastine make it particularly suitable for intranasal or ocular treatment of allergic rhinoconjunctivitis. Peak plasma concentrations (Cmax) occur within 1 to 2 hours of administration of single doses of levocabastine nasal spray and eye drops (0.2mg and 0.04mg, respectively). Drug absorption is incomplete after intranasal and ocular administration, with systemic availability ranging from 60 to 80% for levocabastine nasal spray and from 30 to 60% for the eye drops. However, as the amount of levocabastine applied intranasally and ocularly is small, the levocabastine plasma concentrations achieved are extremely low, with Cmax values in the ranges 1.4 to 2.2 micrograms/L and 0.26 to 0.29 micrograms/L for intranasal and ocular administration, respectively. Pharmacokinetic-pharmacodynamic modelling has indicated that the clinical benefits of levocabastine are predominantly mediated through local antihistaminic effects, although some systemic activity may contribute to the therapeutic efficacy of levocabastine nasal spray during long term use. Levocabastine undergoes minimal hepatic metabolism, i.e. ester glucuronidation, and is predominantly cleared by the kidneys. Approximately 70% of parent drug is recovered unchanged in the urine. Plasma protein binding is approximately 55% and the potential for drug interactions involving binding site displacement is negligible. Furthermore, the pharmacokinetics of this agent do not appear to be influenced by either age or gender. Levocabastine nasal spray and eye drops may thus be considered suitable for the treatment of allergic rhinoconjunctivitis in a wide patient population.
Bioanalysis of Drugs and Metabolites, Especially Anti-Inflammatory and Cardiovascular, 1988
Journal of chromatography, Jan 11, 1979
A method is described for the determination of the antiarrhythmic drug lorcainide hydrochloride a... more A method is described for the determination of the antiarrhythmic drug lorcainide hydrochloride and its three main metabolites in plasma, urine, faeces and tissues from man and animals. The procedure involves the extract of the parent drug, its metabolites and the internal standard from the biological materials at different alkaline pH values, back-extraction into sulphuric acid and re-extraction into the organic phase (heptane--isoamyl alcohol). After silylation of the different phenolic and the N-dealkylated metabolites, analyses were carried out by automated gas--liquid chromatography with electron-capture detection. The method has a sensitivity limit of 5 ng for lorcainide, and 10--20 ng for the various metabolites, per millilitre of plasma. The method was applied to urine, faeces, plasma and tissue samples from man and animals. It was also suitable for automatic sample analysis.
Journal of Chromatography B, 2003
A high-pressure liquid chromatography with ultra-violet detection method for the simultaneous det... more A high-pressure liquid chromatography with ultra-violet detection method for the simultaneous determination of risperidone and 9-hydroxyrisperidone in plasma after liquid-liquid extraction has been developed. The limit of quantitation was 5 nmol / L, and the inter-day coefficient of variation was less than 8% for both compounds. The mean recoveries of risperidone and 9-hydroxyrisperidone added to plasma were 96.8 and 99.4%, with an intra-day coefficient of variation of under 5 and 6%, respectively. Studies of analytical interference showed that the most commonly co-administered antidepressants and benzodiazepines did not interfere. The method was used for the determination of the plasma concentrations of a schizophrenic patient treated daily with an oral dose of 4.5 mg risperidone. The patient suffered severe extrapyramidal side-effects after adding risperidone to his previous medication of haloperidol and levomepromazine. The risperidone plasma concentration was well above the average (182 nmol / L), which suggests that a pharmacokinetic interaction occurred, presumably due to inhibition of the enzyme CYP2D6.
Clinical Cancer Research, 2000
This Phase I study was performed to assess the feasibility of combining docetaxel with the new P-... more This Phase I study was performed to assess the feasibility of combining docetaxel with the new P-glycoprotein inhibitor R101933 and to determine the dose limiting toxicity of this combination. Fifteen patients received oral R101933 alone at a dose escalated from 200 to 300 mg twice daily (b.i.d.; cycle 0), an escalating i.v. dose of docetaxel (60, 75, and 100 mg/m 2 ) as a 1-h infusion (cycle 1), and the combination (cycle 2 and further). Dose limiting toxicity consisting of mucositis and neutropenic fever was reached at the combination of docetaxel, 100 mg/m 2 , and R101933, 300 mg b.i.d., and the maximum tolerated dose was established at docetaxel, 100 mg/m 2 , and R101933, 200 mg b.i.d. Plasma concentrations of R101933 achieved in patients were in the same range as required in preclinical rodent models to overcome paclitaxel resistance. The plasma pharmacokinetics of docetaxel were not influenced by the R101933 regimen at any dose level tested, as indicated by plasma clearance values of 26.5 ؎ 7.78 liters/h/m 2 and 23.4 ؎ 4.52 liters/h/m 2 (P ؍ 0.15) in cycles 1 and 2, respectively. These findings indicate that the contribution of a P-glycoprotein inhibitor to the activity of anticancer chemotherapy can now be assessed in patients for the first time independent of its effect on drug pharmacokinetics.
Ketoconazole is an orally effective, broad-spectrum, systemic antifungal agent. The pharmacokinet... more Ketoconazole is an orally effective, broad-spectrum, systemic antifungal agent. The pharmacokinetics and bioavailability of ketoconazole given as a 200-mg single dose in a tablet, suspension, or solution were studied in 24 fasting healthy males by using a crossover design. Levels of ketoconazole in plasma were determined for up to 48 h by a sensitive reverse-phase high-performance liquid chromatography method. The absorption of ketoconazole was rapid, with mean maximum concentrations of the drug in plasma of 4.2, 5.0, and 6.2 ,g/ml attained at 1.7, 1.2, and 1.0 h, respectively, after administration of the tablet, suspension, and solution, respectively. The mean distribution and elimination half-life values were 1.5 to 1.7 and 7.5 to 7.9 h, respectively. The mean oral clearance of the solution dose was 209 (+82.9 [standard deviation]) ml/min, and the mean apparent volume of distribution was 88.31 (±68.72) liters. The relative bioavailabilities for the tablet and suspension were 81.2 (±33.5) and 89.0 (±23.1)%, respectively, of that of the solution. The data indicated the bioequivalence of the tablet to the suspension and of the suspension to the solution. Dose proportionality of ketoconazole was also studied in 12 volunteers after they received solution doses of 200, 400, and 800 mg. Linear correlations between the dose and the maximum concentration of the drug in plasma, the time to the maximum concentration, and the area under the concentration-time curve were observed. However, the increase in the area under the curve was more than proportional to the dose given. The levels in plasma seemed to decay at a lower rate after 400and 800-mg doses. The mean oral clearance decreased from 244.9 to 123.6 and 80.0 ml/min, respectively, as the dose increased from 200 to 400 and 800 mg. The apparent dose-dependent kinetics may have been due to the presystemic elimination and capacity-limited hepatic metabolism which become saturated at higher doses.
Clinical cancer research : an official journal of the American Association for Cancer Research, 2000
This Phase I study was performed to assess the feasibility of combining docetaxel with the new P-... more This Phase I study was performed to assess the feasibility of combining docetaxel with the new P-glycoprotein inhibitor R101933 and to determine the dose limiting toxicity of this combination. Fifteen patients received oral R101933 alone at a dose escalated from 200 to 300 mg twice daily (b.i.d.; cycle 0), an escalating i.v. dose of docetaxel (60, 75, and 100 mg/m2) as a 1-h infusion (cycle 1), and the combination (cycle 2 and further). Dose limiting toxicity consisting of mucositis and neutropenic fever was reached at the combination of docetaxel, 100 mg/m2, and R101933, 300 mg b.i.d., and the maximum tolerated dose was established at docetaxel, 100 mg/m2, and R101933, 200 mg b.i.d. Plasma concentrations of R101933 achieved in patients were in the same range as required in preclinical rodent models to overcome paclitaxel resistance. The plasma pharmacokinetics of docetaxel were not influenced by the R101933 regimen at any dose level tested, as indicated by plasma clearance values o...
Pharmacotherapy
The bioavailability of risperidone was evaluated in an open-label, randomized, two-way, crossover... more The bioavailability of risperidone was evaluated in an open-label, randomized, two-way, crossover study comparing a 1-mg tablet with a 1-mg/ml oral solution. Both formulations were administered as a single 1-mg dose with a 10-day washout period between treatments. Of 26 healthy men who entered the study, 23 completed both treatment periods. Plasma concentrations of risperidone and the active moiety (risperidone plus its active metabolite, 9-hydroxyrisperidone) were determined by radioimmunoassays. For key pharmacokinetic values (Cmax, AUC), the 90% CIs on the relative bioequivalence of risperidone, 9-hydroxyrisperidone, and the active moiety were contained within the equivalence range of 80-120% (80-125% for log-transformed data). The results demonstrate that the 1-mg/ml oral solution and the 1-mg tablet are bioequivalent.
Clinical Pharmacology and Therapeutics, 1984
Alfentanil disposition after an intravenous bolus of 50 pglkg was followed in 15 elderly surgical... more Alfentanil disposition after an intravenous bolus of 50 pglkg was followed in 15 elderly surgical patients and was compared to that in nine young adults. A two-compartment open model described alfentanil disappearance from plasma. Apparent volumes of distribution of the central compartment (201 and 211 ml/kg; k), at steady state (460 and 543 ml/kg), and of the AUC (746 and 722 ml/kg) in young adults and in elderly subjects did not differ. Plasma clearance was lower in elderly subjects (4.4 ml/mm/kg) than in young adults (6.5 ml/mm/kg), whereas terminal plasma t1/2 was longer in the elderly patients (137 and 83 min). Alfentanil dosage should therefore be reduced in elderly patients when large single doses, multiple doses, or long-term infusions are required.
Pharmacy World amp; Science, 1993
Pharmaceutisch Weekblad, 1987
Pediatric Hematology-Oncology, 1989
Two consecutive nonrandomized studies were conducted in children with prolonged granulocytopenia ... more Two consecutive nonrandomized studies were conducted in children with prolonged granulocytopenia to evaluate the prophylactic antifungal activity of ketoconazole and the new triazole itraconazole. The conditions were equivalent in both studies. The incidence of colonization was 10% in the ketoconazole group and 19% in the itraconazole group (this difference is not significant). For suspected and proven infections, the incidence was 5% for ketoconazole and 10% for itraconazole, but the incidences were too low for statistical comparison. Although the colonization rate was higher for itraconazole, there was no sign of Aspergillus, whereas in the ketoconazole group an autopsy, proven aspergillosis has been reported.
Journal of Veterinary Pharmacology and Therapeutics, 1988
with R 81 101 fentanyl in the dog: pharmacodynamic and pharmacokinetic interactions. J . vet. Pha... more with R 81 101 fentanyl in the dog: pharmacodynamic and pharmacokinetic interactions. J . vet. Pharmacol. Therap. 11, 63-70. The pharmacokinetics and clinical effects of the short-acting hypnotic R 81 10 and of the narcotic analgesic fentanyl were studied in the dog. T h e effects of separate intravenous (i.v.) injections of R 81 10 (4 mg/kg) and fentanyl(O.015 mg/kg) and of concurrent i.v. injection of the two were studied. After administration of R 81 10, induction of hypnosis occurred within 1 min, maximal depth of anaesthesia and satisfactory analgesia and muscle relaxation were obtained after 5 min. The effects had decreased within 15 min and full recovery occurred within 30 min. Fentanyl alone produced neither hypnosis nor muscle relaxation. When fentanyl and R 81 10 were given simultaneously, the duration of hypnosis was doubled in comparison with R 81 10 alone. Moreover, markedly improved and longer lasting analgesia and muscle relaxation were observed with the combination. When the drugs were injected together, the plasma concentrations of R 8110 were initially much higher than after separate injection of R 8110, but they became similar after 30 min. Although statistically non-significant, fentanyl reduced the total plasma clearance of R 81 10 (31.1 f 6.9 vs. 21.9 k 2.3 mVkg/min) and decreased the volume of distribution (3.78 k 1.83 vs. 2.23 k 0.90 Vkg, P < 0.05). Fentanyl did not alter the elimination half-life of R 81 10. R 81 10 had no apparent influence on the pharmacokinetics of fentanyl.
Biological Mass Spectrometry, 1989
The Journal of Clinical Pharmacology, 1993
The effects of renal insufficiency and hemodialysis on the pharmacokinetics of orally administere... more The effects of renal insufficiency and hemodialysis on the pharmacokinetics of orally administered levocabastine were studied in six nondialysis patients and in six patients undergoing regular hemodialysis. Levocabastine .5 mg, supplied as a solution, was administered orally to each patient 1 hour after breakfast. Compared with data in healthy volunteers, the oral absorption and disposition of levocabastine were impaired in patients with renal insufficiency. The time to reach peak plasma concentration was increased and the peak plasma concentration was decreased in the patients with renal insufficiency compared with healthy volunteers. Urinary excretion of the unchanged drug, which is the major elimination pathway of levocabastine, was reduced in the patients with renal insufficiency. The decreased urinary excretion most likely contributed to the prolonged half-life (from 36 hours to 95 hours) and increased area under the plasma concentration-time curve (+56%) in the patients with renal insufficiency as compared with the healthy volunteers. Although the 6-hour hemodialysis procedure starting 4 hours after dosing eliminated 10% of the oral dose, the terminal half-life and the total area under the plasma concentration-time curve did not differ significantly between the hemodialysis and the nonhemodialysis patients. In conclusion, the current study showed that the initial oral absorption of levocabastine is reduced and that levocabastine elimination is prolonged in patients with renal insufficiency.
The Journal of Clinical Pharmacology, 1998
A randomized, open-label, comparative study was conducted in 30 male patients with moderately adv... more A randomized, open-label, comparative study was conducted in 30 male patients with moderately advanced human immunodeficiency virus (HIV) infection to examine the pharmacokinetics of an investigational intravenous preparation of itraconazole compared with pharmacokinetics after administration of itraconazole capsules. The study also assessed whether adequate plasma concentrations of itraconazole could be rapidly achieved with the intravenous formulation and then maintained after cessation of intravenous therapy with itraconazole capsules. All patients received 200 mg intravenous itraconazole as a 1-hour infusion in 40% hydroxypropyl-beta-cyclodextrin (HP-beta-CD) vehicle twice daily for 2 days, and then 200 mg intravenously once daily for 5 days. Patients then received itraconazole capsules, either 200 mg twice daily or 200 mg once daily for 28 days. Steady-state plasma concentrations of itraconazole were reached by day 3 with intravenous infusion, a much shorter time than observed with administration of itraconazole capsules. Steady-state concentrations of itraconazole and hydroxyitraconazole were effectively maintained during the rest of the intravenous infusions of itraconazole. Oral follow-up with administration of 200-mg capsules once daily could not maintain the plasma concentrations of itraconazole and hydroxyitraconazole obtained at the end of the intravenous treatment, whereas twice-daily oral administration maintained or increased these concentrations. Mean plasma concentrations of itraconazole and hydroxyitraconazole on day 7 were similar to those on day 36 in the twice-daily group. Mean renal clearance was comparable to mean total body clearance, and approximately 93% to 101% of the HP-beta-CD was excreted unchanged in urine within 12 hours of administration. The HP-beta-CD was essentially eliminated through the kidney, and little accumulation in the body was observed in this patient population. Adverse events during the intravenous phase were most commonly associated with intravenous administration. Intravenous infusion of itraconazole for 7 days followed by administration of itraconazole capsules twice daily for 28 days is an effective dose regimen in patients with advanced HIV infection.
Pharmacy World & Science, 1983