Pharmacokinetics of methadone and its primary metabolite in 20 opiate addicts

In a closed metabolic ward the pharmacokinetics of methadone and its primary metabolite (EDDP) were studied in 20 long-term opiate addicts. After administration of the daily oral dose of methadone HCl (mean 60 mg, range 10–225 mg) blood samples were taken and analysed, using a newly developed high-performance liquid chromatography (HPLC) method. The steady-state plasma concentrations of the 20 subjects varied from 65–630 ng·ml^–1 and from 5 to 55 ng·ml^–1, whereas the peak concentrations were 124–1255 ng·ml^–1 and 10 – 301 ng·ml^–1 for methadone and EDDP, respectively. The calculated ratios between the area under the curve (AUC_{(0–24 h)}) for methadone and the AUC_{(0–24 h)} for EDDP varied from 5.9 to 44.6, indicating interindividual differences in metabolic activity. In 19 out of 20 subjects the pharmacokinetics of methadone are best described using a two-compartment model. The mean body clearance was 1.64 ml·min^–1·kg^–1, whereas the mean elimination rate constant () and plasma half-life (t _1/2) were 0.026·h^–1 (range 0.013–0.053·h^–1) and 31.2 h (range 13–53 h), respectively. Differences of gender were also found. A poor correlation was found between the methadone dose and the steady-state level. A much better correlation was found between the normalized steady-state level and the body clearance.     

Pharmacokinetics of the oral narcotic analgesic bezitramide and preliminary observations on its effect on experimentally induced pain

Summary The oral absorption of bezitramide 5 mg was studied in 7 human volunteers, using a specific radioimmuno-assay which measured both bezitramide and its active metabolite R-4618. A lag time of 0.5–1.0 h and a C_max of 5.4 ng/ml plasma were found, the latter occurring 2.5–3.5 h after administration. The apparent elimination half-life varied from 11 to 24 h. Less than 0.3% of the dose was excreted unchanged in the urine. High concentrations in the faeces of some individuals indicate incomplete absorption and/or biliary secretion. The analgesic effect, using a standardized superficial electrical stimulation method, reached its maximum between 2.5 and 3.5 h after dosing, in accordance with the absorption phase. The duration of the effect was highly variable. Experiments in rats (n=6,³H-bezitramide 2.5 µg), demonstrated extensive biliary excretion (up to 70% of total radioactivity) and less than 3% of the label was removed by urinary excretion.     

Pharmacokinetics of ketoprofen following single oral,intramuscular and rectal doses and after repeated oral administration

Summary The pharmacokinetics of ketoprofen was studied in the same healthy subjects after single oral, intramuscular and rectal doses, and after repeated oral administration. No significant difference in the mean t_1/2 (1.13–1.27 h) was observed after the different modes of administration. The mean [AUC] ₀ after rectal administration of a suppository showed the minimum significant difference (p<0.05) from that after oral administration of the capsule. The apparent volume of distribution (Vd/F) was approximately 10–15% of body weight. The renal contribution (mean, 0.10–0.15 ml/min/kg) to the plasma clearance of free ketoprofen was assumed to be, at most, 8.3–12.9%. The projected cumulative excretion of total (free plus conjugated) ketoprofen via urine exceeded 63–75% of the dose, of which approximately 90% was ketoprofen glucuronide. A mean of 71–96% and 73–93% of the oral capsule was estimated to be systemically available after administration of the intramuscular preparation and rectal suppository, respectively. In four of seven subjects, CPK concentration was elevated after the intramuscular injection. The mean steady-state concentration of ketoprofen in plasma ranged from 0.43 to 5.62 µg/ml after the final dose of a 50 mg q.i.d. regimen. The disposition data and plasma levels observed at steady-state were in agreement with those predicted from the single oral dose study. The accumulation ratio was 1.08±0.08. The results suggest that the rectal suppository can be recommended as an extravascular mode of administration of this drug.A preliminary account of this work was presented at the 10th Congress of Japanese Society of Clinical Pharmacology, Sapporo, 27 August 1979     

The bioavailability of Tamoplex? (tamoxifen)

The bioavailability of two tamoxifen preparations (Tamoplex^® and Nolvadex^®) was compared in a multiple dose two-way cross-over design in twelve breast cancer patients. The formulations were found to be bioequivalent. Mean steady-state serum levels of tamoxifen andN-desmethyltamoxifen were 133 ng/ml and 242 ng/ml, respectively, at a single daily dose of three tablets of Tamoplex^® 10 mg and 128 ng/ml and 248 ng/ml, respectively, at a single daily dose of three tablets of Nolvadex^® 10 mg. While there was a large interpatient as well as intrapatient variability in steady-state levels of tamoxifen andN-desmethyltamoxifen, their ratio appeared to be constant in the individual patient.     

Rectal pharmacokinetics of budesonide

The pharmacokinetics and systemic availability of budesonide after rectal administration of two single enema doses (2 mg in 100 ml fluid of almost identical composition) were compared in 15 healthy volunteers. In 11 of these subjects, 2 mg oral budesonide in a gelatine capsule was given on a separate occasion. An intravenous administration (0.5 mg) was given as reference. With this design, individual hepatic bypass of the rectally administered budesonide dose could be estimated. The pharmacokinetics of the two enema formulations were similar, although not bioequivalent. Mean systemic availability was 16% (range 4.2–43%) and 15% (3.2–50%) after rectal administration and 6.3% (2.4–10%) after oral administration. The rectal data revealed a small intra- but a substantial inter-subject variability in systemic availability. C_max was 3.3 nmol·l^-1 (0.95–8.2), 3.0 nmol·l^-1 (0.64–8.9) and 1.3 nmol·l^-1 (0.61–3.0), respectively, for the three formulations. Absorption was rapid and essentially terminated within 3 h after rectal dosing [t_max=1.3 h for both formulations (range 0.5–2.0)], but was slower after oral dosing [t_max=2.1 h (1.0–6.0)]. If a complete absorption after oral and rectal dosing is assumed, the fraction of the rectal dose entering the liver at first pass can be calculated to be 88% (55–99%).The higher systemic availability and intersubject variability after rectal dosing does not seem to be caused by differences in first-pass liver metabolism but rather by hepatic bypass of a varying portion of administered drug. This portion seems to be typical for an individual and might be explained by anatomical differences between subjects.     

Effect of Vehicles and Penetration Enhancers on the In Vitro and In Vivo Percutaneous Absorption of Methotrexate and Edatrexate Through Hairless Mouse Skin

Purpose. Low-dose methotrexate (MTX) is approved for the treatment of recalcitrant rheumatoid arthritis (RA). The objective of this study was to determine the effect of vehicles and penetration enhancers on the percutaneous absorption of MTX and its analog edatrexate (EDAM), and develop transdermal (TD) delivery systems of the drugs for the treatment of RA. Methods. From previously published pharmacokinetic parameters with low-dose MTX therapy, and considering a 50 cm² diffusional area, the target steady state in vitroTD flux for MTX was calculated to be 35 g/cm²/hr. Modified Franz diffusion chambers and hairless mouse skin were used for in vitro skin permeation studies. Hairless mice were used for in vivo studies. Delivered amounts of MTX and EDAM were determined by assaying the receiver phase fluid (or blood) with validated reversed phase HPLC methods. Results. Intrinsic partition coefficient of MTX was low (log P = –1.2). Target MTX fluxes of 35 g/cm²/hr were achievable only with 1–15% (v/v) Azone^® in propylene glycol (PG). Flux of EDAM (85 g/cm²/hr) was higher than MTX from an isopropyl alcohol (IPA)—5% (v/v) Azone^® system. Clinically significant steady state in vivo blood concentration of MTX and EDAM was achieved using delivery systems containing 2.5% Azone^® in PG. Area under the drug concentration-time curves (AUC_0–24hr) for MTX were 2379 and 3534 ng*hr/ml from PG—2.5% Azone^® and PG—7.5% Azone^® systems respectively. AUC_0-24hr of EDAM was 6893 ng*hr/ml using a PG—2.5% Azone^® system. Conclusions. Results of this study show the feasibility of using a transdermal delivery system of MTX and EDAM for the treatment of rheumatoid arthritis.     

Preliminary study on the absorption profile after rectal and oral administration of methadone in human volunteers

Methadone is a potent, long acting narcotic analgesic which can be orally administered due to its almost complete bioavailability. There is a growing interest in the rectal route of administration in the case of acute postoperative or chronic malignant pain. Since virtually no data were available on the rectal absorption profile of methadone in man, plasma concentrations of methadone were determined by means of HPLC analysis after a single dose of 10 mg methadone HCl in a cross-over pilot study in five volunteers. The rectal dosage forms included aqueous solutions and fatty suppositories. A comparison was made with an orally administered solution. Compared with oral dosing, the extent of rectal absorption from an aqueous solution was almost 80% up to 8 h after dosing. Although the mean peak concentration and the AUC_0-8h was significantly lower (p < 0.01), no marked difference in t_max was observed: 2.8 and 3.1 h respectively. Rectal absorption conditions of methadone from fatty suppositories (3 ml) were found to be less favourable. The peak plasma concentration was only reached 3–4 h after administration, whereas the relative bioavailability up to 8 h after dosing ranged from 35–58%. This rate-limiting absorption pattern may be due to the critical solubility properties of methadone HCl at physiological pH.     

Absorption kinetics of oral and rectal flecainide in healthy subjects

Summary The absorption kinetics of different pharmaceutical formulations of orally and rectally administered flecainide have been assessed in a cross-over study in 7 healthy volunteers. The subjects received single doses of flecainide after a washout period of at least one week. A tablet, an oral solution, a rectal solution and a 10 min i.v. infusion during 10 min each containing 100 mg flecainide were administered to the subjects in a randomized order.The mean absolute bioavailability was 98%, 78% and 81% for the rectal and oral solutions and the tablet. The lag time after administration of the oral solution was 0.33 h and it was 0.86 h after the tablet and 0.18 h after the rectal solution. The mean time to the peak serum concentration (t_max) after the rectal solution (0.67 h) was shorter than after either the tablet (4 h) or oral solution (1 h). The maximum serum concentration (C_max) was 0.29 mg · 1^–1 after the rectal solution, 0.14 mg · 1^–1 after the tablet and 0.17 mg · 1^–1 after the oral solution. All the volunteers showed significantly higher serum flecainide concentrations during the first 20 min of the absorption phase after rectal administration of 100 mg flecainide as a solution compared to its oral administration.In conclusion: based on the absolute bioavailability, C_max, t_max, and lag times, rectal administration of flecainide solution gave a better absorption profile than after oral tablet or solution.     

Kinetics of ergotamine after intravenous and intramuscular administration to migraine sufferers

Summary The kinetics of ergotamine has been investigated in migrainous patients using a new, specific, sensitive HPLC assay (detection limit 100 pg/ml plasma). 10 patients were given ergotamine tartrate 0.5 mg i.v. and 5 of them received the same dose i.m. 2–3 weeks later. Blood samples were collected for up to 54 h following administration and the plasma concentration were analysed. After intravenous administration the plasma ergotamine declined rapidly, with an initial distribution half-life of 3 min followed by a mean terminal half-life of 1.86 h (range 90–155 min). The mean total plasma clearance was 11.0 ml kg^–1 min^–1, and the volume of distribution (V_d ) was 1847.6 ml kg^–1. Individual t_1/2 showed a positive linear correlation with the individual V_d . The intramuscular absorption of ergotamine was rapid and maximum plasma levels were usually obtained 10 min following administration. The biological availability was incomplete and variable at 46.6% (range 28.3–60.8%).     

Chronopharmacokinetics of theophylline after sustained release and intravenous administration to adults

Summary The influence of time of drug administration on pharmacokinetics of theophylline was studied both after ingestion of a sustained-release tablet, containing choline theophyllinate (Zy 15061-S. R.; Teovent^®; Sabidal^®; ZYMA S.A.) and after intravenous infusion of aminophylline to eight healthy volunteers. Both drugs were administered in the morning (10 a.m.) and on a separate occasion in the evening (10 p.m.) after a 12 h period of fasting.After oral administration of a dose of 540 mg theophylline, the drug was steadily absorbed, both during day-time and during night-time. In some subjects absorption was slower in the evening. Maximum theophylline plasma concentrations were reached after 3.3±0.4 h (mean±SD) and 3.9±1.4 h respectively (not significantly differentp>0.05).The maximum plasma concentrations were almost identical after administration in the morning and in the evening (12.6±3.3 mg·l^–1 and 13.1±1.4 mg·l^–1 respectively).There was also no significant difference (p>0.05) between the areas under the plasma concentration-time curves after oral and intravenous administration, both at day-time and at night-time. This finding indicates complete bioavailability of the sustained release tablets on both occasions.After administration of the tablets in the morning the plasma concentration 12 h post dosing was significantly lower than after administration in the evening: c ₁₂ ¹ accounted for 6.0±2.0 mg·l^–1 after intake at 10 a.m. and for 7.9±2.1 mg·l^–1 after ingestion at 10 p.m. (p<0.01).A similar observation was done after intravenous administration of the drug: c₁₂ was 6.6±1.6 mg·l^–1 after starting the infusion in the morning and 8.0±1.8 mg·l^–1 after infusing the drug in the evening (p<0.01). This phenomenon could be explained by the finding of a significantly prolonged half-life of theophylline during night-time, provided that the plasma concentrations were in the range of 5 to 15 mg·l^–1 (which coincides approximately with the therapeutic range of the drug). For day-time elimination the half-life of theophylline was found to be 6.2±0.9 h and for night-time elimination 8.0±2.0 h (p<0.01), which means an increase of 29.6±20.9% during the night. The prolonged half-life of theophylline at night-time might be of therapeutic benefit in preventing bronchus obstruction in the morning.     

Studies on hydralazine

Summary After oral administration of a single 50 mg dose of hydralazine (Apresoline^®), the serum half-life (T1/2) and bioavailability (AUC_0–) were assessed in 16 healthy volunteers. The half-life was 2.57±0.14 h (S.E.) in 10 slow acetylators of sulphadimidine, and 2.18±0.15 h in 6 fast acetylators (difference not statistically significant). AUC_0– was significantly higher in slow acetylators, at 1.04±0.10 µg·hour·ml^–1, compared to 0.66±0.12 µg·hour·ml^–1 in the fast acetylators (p<0.025). Treatment with Apresoline^® 25 mg tid produced minimum serum concentrations at steady-state of 57.3±7.3 ng·ml^–1 and 33.4±4.2 ng·ml^–1 in 8 slow and 5 fast acetylators, respectively (p<0.05). The corresponding maximum concentrations were 228.8±20.3 ng·ml^–1 and 147.6±15.0 ng·ml^–1 in slow and fast acetylators, respectively (p<0.025). First-pass metabolism of hydralazine could explain the difference in bioavailability of the drug between fast and slow acetylators, without any corresponding difference in the elimination rate of the drug in the post-distributive phase.     

Pharmacokinetics of cefonicid in children

Summary The pharmacokinetics of cefonicid was studied in 17 children requiring antibiotic treatment for respiratory or urinary tract infections. After informed consent had been obtained from the parents, a single dose of cefonicid 50 mg/kg/body weight was given by intramuscular injection.The mean peak serum concentration of 212.63 µg/ml was reached at 1.00 h, as absorption occurred at a very fast rate with a mean constant of 3.24 h^–1. Mean values for half-life, apparent volume of distribution (V_z), total body clearance (CL), and renal clearance (CL_R) were 3.24 h, 0.21 l·kg^–1, 16.67 ml·min^–1 and 13.60 ml·min^–1 respectively. There was an inverse relationship between age and V_z, whereas CL and CL_R were positively correlated with age. Cefonicid concentrations in urine were many times higher than the MICs of susceptible strains of bacteria.The study demonstrated that i.m. cefonicid 50 mg·kg^–1 gave serum concentrations well within the therapeutic range for susceptible bacteria, and that its pharmacokinetic properties allow single daily doses to be used to treat infections in children.     

Pharmacokinetic interactions of timolol with vasodilating drugs,food and phenobarbitone in healthy human volunteers

Summary Pharmacokinetic interactions of oral timolol maleate 10 mg, with food (3566 kJ), single oral doses of prazosin 1 mg and dihydralazine 25 mg, and with a 1 week pretreatment with phenobarbitone 100 mg daily were examined in a randomized crossover study in 12 healthy volunteers. After fasting, the peak level (C_max=29.1±3.2 ng/ml; mean±SEM) was reached at 1.3±0.1 h (T_max). The total area under the serum concentration-time curve (AUC^0–) was 154.4±33.8 ng×h/ml, total clearance (Cl_tot) 751.5±90.6 ml/min, renal clearance (Cl_ren) 97.2±10.1 ml/min, elimination half-life (t_1/2) 2.9±0.3 h and 24-h recovery in urine (X _u ^0–24 ) 11.1±1.4% of the dose. Food and prazosin did not significantly affect the fate of timolol maleate. Dihydralazine enhanced C_max (38.2±4.6 ng/ml) only when compared to phenobarbitone treatment, and did not affect any other parameters. Phenobarbitone pretreatment somewhat lowered C_max (25.5±3.9 ng/ml), AUC^0– (117.5±22.1;p<0.05 vs food) and X _u ^0–24 (8.7±1.2%), evidently by increasing Cl_tot (957.5±116.9 ml/min;p<0.05 vs food), but it did not affect Cl_ren. It is concluded that the pharmacokinetics of timolol maleate can be altered to a limited extent in opposite directions by dihydralazine and phenobarbitone.     

Pharmacokinetics of N-acetylcysteine following repeated intravenous infusion in haemodialysed patients

Objective N-acetylcysteine (NAC) is a mucolytic agent with anti-oxidant properties. It might have potential positive effects in renal patients and, therefore, its pharmacokinetics and safety in haemodialysis was investigated.Methods Twelve dialysis patients received 2 g NAC (10 ml NAC 20% solution i.v.) mixed with 500 ml saline during the first 3 h of the session for six dialysis sessions. A bolus of heparin was injected intravenously as LWH-heparin. In six patients, one session was repeated with NAC mixed with heparin and infused through the heparin pump.Results Baseline NAC was on average 454 ng ml^–1; its concentration increased to 9,253 ng ml^–1 at the second infusion and attained a steady state between 14,000 ng ml^–1 and 17,000 ng ml^–1 at the fourth dose. We observed a C _max of 53,458 ng ml^–1 with a t _max of 3.0 h. Plasma clearance was 1.25 l h^–1 and dialytic clearance 5.52 l h^–1. No side effects were observed.Conclusion In the case of repeated doses, the NAC pre-dose concentration after repeated infusion of 2 g of the drug during the first 3 h of a dialysis session reached the steady state at the fourth infusion, without further accumulation. The dialytic clearance is effective, the total body clearance being reduced to 1.25 l h^–1. In dialysis patients, 2 g NAC given intravenously over 3 h is a safe dosage, with no short-term side effects.The study was conducted in accordance with the guidelines for Good Clinical Practice and all current Swiss laws concerning clinical research. The protocol was approved by the Ethics Committee of the Canton Ticino, Switzerland.     

A Pharmacokinetic Model of Intravenously Administered Hyaluronan in Sheep

Hyaluronan (HA; hyaluronic acid) is produced in the interstitium and reaches the blood circulation through the lymph. It is rapidly eliminated by means of specific receptors on liver endothelium. The elimination characteristics of intravenously administered HA were studied in 10 conscious sheep at the normal plasma HA concentration by injection of a ³H-labeled tracer and at a very high concentration by an i.v. infusion of unlabeled HA and simultaneous injection of a tracer dose of ³H-labeled HA. At a normal plasma HA concentration (0.12 ± 0.05 µg/ml; range, 0.072–0.228 µg/ml), the apparent T _1/2 of ³H-HA was 5.3 ± 1.1 min (range, 3.3–6.5 min). At higher plasma concentrations (range, 1.83–3.35 µg/ml), the apparent T _1/2 was considerably prolonged (range, 18.2–43.5 min). A one-compartment, nonlinear model was fitted to data obtained from the bolus-infusion study of unlabeled HA. The Michaelis–Menten constant, K _m , was 0.12 ± 0.04 µg/ml, indicating that a deviation from linear kinetics will occur when the normal plasma concentration is exceeded. The V _max was 0.062 ± 0.009 µg/ml/min. Three-dimensional surface plots showed that the plasma HA concentration and the total hepatic plasma flow influence the apparent metabolic clearance, extraction ratio, turnover, and T _1/2 of intravenously injected hyaluronan. There was a high correlation between T _1/2 as measured by the injected ³H-HA and T _1/2 calculated from the model (r = 0.96).     

Pharmacokinetics of theophylline in patients following short-term intravenous infusion

Summary Serum theophylline concentrations after intravenous administration of a new short-term infusion (Euphyllin^® Kurzzeitinfusion) were measured in 50 out-patients with chronic obstructive airways disease (COAD). An intravenous infusion of theophylline ethylenediamine 480 mg (corresponding to approximately 350 mg anhydrous theophylline) in 50 ml isotonic solution was given in 20 min. Blood samples were taken beforehand and 25 to 30 min and 1, 3 and 6 h after starting the infusion. 86% of the patients had a one-hour serum level in the therapeutic range of 8–20 mg/l, and 2 h later, this was true of 64% of the patients. The short-term infusion was well tolerated, even in cases with unknown high pre-infusion serum levels. Pertinent pharmacokinetic parameters were determined, such as total body clearance, apparent volume of distribution, and half-life of elimination. Geometric mean and 95%-confidence limits, derived from the log-normal distribution of these parameters, were: Cl=0.044 (0.018–0.109) l/h/kg ideal body weight, V_d=0.451 (0.258–0.789) l/kg ideal body weight, and t_1/2(el)=7.1 (2.6–19.1) h.     

Pharmacokinetics of lidocaine and its deethylated metabolite: Dose and time dependency studies in man

The concentrations of lidocaine and of its deethylated metabolite, MEGX, were measured in blood following the intravenous administration of 50 and 100 mg lidocaine hydrochloride, the oral administration of 100, 300, and 500 mg lidocaine hydrochloride monohydrate, and the oral administration of 300 mg lidocaine hydrochloride monohydrate every 8 h for seven doses, to three healthy volunteers. The range of values for the parameters defining the disposition kinetics of lidocaine were: terminal half-life, 50–231 min; total clearance, 13–17 ml/min/kg; initial dilution space, 0.13–2.5 liters/kg; and volume of distribution at steady state, 0.6–4.5 liters/kg. Lidocaine absorption from solution was rapid, but due to presystemic hepatic metabolism, the availability was low, the range of average values lying between 0.19 and 0.38. No dose or time dependency in lidocaine and monoethylglycinexylidide pharmacokinetics following the single dose studies of lidocaine were noted. Effective hepatic blood flow, based on total clearance and availability measurements, was estimated to be 18–27 ml/min/kg. The concentrations of MEGX were approximately one-third of those of lidocaine following intravenous lidocaine and were comparable following oral lidocaine, but as predicted, the dose normalized area under the MEGX concentration-time curve was constant and independent of the route of administration of lidocaine. In two subjects, the blood concentrations of lidocaine and MEGX following multiple doses of oral lidocaine were those predicted from the single dose studies. In the third subject, the degree of accumulation of lidocaine was greater than predicted. The reasons and mechanism for this difference between subjects on multiple dosing remains unclear.Glossary ₁, ₂ exponential coefficients associated with the first and second phase of the biexponential equation describing lidocaine disposition; min^–1 - ANOVA analysis of variance - AUC total area under the blood drug concentration-time curve; (mg/liter) × min - CL total (blood) clearance of lidocaine; ml/min/kg - EHBF effective hepatic blood flow; ml/min/kg - F oral availability of lidocaine - f _m fraction of lidocaine converted to MEGX which appears in the general circulation. MEGX monoethylglycinexylidide - t _1/2,1 t _1/2,2 half-life associated with the first and second phase, respectively, of lidocaine disposition; min - t _1/2,abs absorption half-life of lidocaine; min - t _1/2,MEGX elimination half-life of MEGX; min - tlag time between administration and estimated start of lidocaine absorption; min - V ₁ initial dilution space of lidocaine; liters/kg - V volume of distribution of lidocaine during the terminal phase; liters/kg - V _ss volume of distribution of lidocaine at steady state; liters/kg - V _MEGX volume of distribution of MEGX; liters/kg     

The pharmacokinetics of eflornithine (α-difluoromethylornithine) in patients with late-stage <Emphasis Type="Italic">T.b. gambiense</Emphasis> sleeping sickness

Objective To investigate the plasma, cerebrospinal fluid (CSF) levels and pharmacokinetics of eflornithine (DFMO) in patients with late-stage T.b. gambiense sleeping sickness who were treated with an oral DFMO at 100 mg/kg or 125 mg/kg body weight every 6 h for 14 days.Methods Plasma and CSF concentrations of DFMO were measured during day 10 and day 15 in patients following oral DFMO at 100 mg/kg (group I: n=12) and 125 mg/kg (group II: n=13) body weight every 6 h for 14 days. Clinical and parasitological assessments were performed at 24 h after the last dose of DFMO and at 12 months.Results Patients in each group had a good initial response, but relapse was observed in six patients (three patients for each group) during 12 months follow-up. Plasma DFMO concentrations did not increase proportionally to doses when the dose increased from 100 mg/kg to 125 mg/kg body weight given every 6 h (60–70% of the expected increase). In most cases, concentration–time profiles of DFMO in each group were best fit using a two-compartment open model with first-order input, with absorption lag-time and first-order elimination. Average trough (C_ss-min) and average (C_ss-ave) plasma DFMO concentrations during steady state varied between 189–448 nmol/ml and 234–528 nmol/ml, following 100 mg/kg and 125 mg/kg dose group, respectively. C_max, t_max and AUC_0– values following the last dose were 296–691 nmol/l, 2–3 h, and 2911–6286 nmol h/ml, respectively. V_z/F, CL/F and t_1/2z values were 0.47–2.66 l/kg, 0.064–0.156 l/h/kg, and 3.0–16.3 h, respectively. CSF concentrations at steady state varied between 22.3 nmol/ml and 64.7 nmol/ml. Patients who had treatment failure tended to have lower plasma and CSF DFMO concentrations than those who had successful treatment.Conclusion Oral DFMO at the dose of 125 mg/kg body weight given every 6 h for 14 days may not produce adequate therapeutic plasma and CSF levels for patients with late-stage T.b. gambiense sleeping sickness.     

Serum concentrations and clinical effect of zuclopenthixol in acutely disturbed,psychotic patients treated with zuclopenthixol acetate in Viscoleo®

Zuclopenthixol acetate, 5%, in Viscoleo^sR was administered IM to 19 acutely disturbed, psychotic patients in doses of 50–150 mg. Fifteen patients received one injection, whereas four of the patients had two or three injections, usually with intervals of 3 days. The zuclopenthixol concentrations in serum were measured in series of samples taken from each patient during a 3-day period following the injection. In patients given identical doses serum concentrations of about the same order were obtained. Significant and good correlations were found between dose and maximal serum concentration and between dose and area under the serum concentration curve. The average serum concentration curve obtained when adjusting the data to a 100 mg dose has a maximum of 41 ng/ml after about 36 h, decreasing to 15 ng/ml after 72 h.A dose of 50–150 mg zuclopenthixol acetate in Viscoleo^® appeared to be sufficient for controlling the symptoms for most acutely disturbed, psychotic patients. The frequency of side effects, including extrapyramidal reactions, was low and the adverse reactions mostly mild, indicating that the risks for severe complications generally might be minimal. With a rapid onset of action, few and mild side effects, good tolerability at the injection site, and a duration of effect of 2–3 days, zuclopenthixol acetate in Viscoleo^® appears to offer advantages compared to conventional neuroleptic treatment in patients in whom an acute, calming effect is desired.     

Modeling of the Saturable Time-Constrained Amoxicillin Absorption in Humans

Amoxicillin pharmacokinetics was modeled using a two-compartment disposition model and a saturable time-constrained absorption model with a storage compartment. The absorption model parameters estimated by the nonlinear regression are: a rate constant of the systemic input, k_sys, (median: 1.31 h^–1, range: 0.79–7.01 h^–1), a maximal absorption rate, V_ma, (median: 1407 mg/h, range: 703–4181 mg/h), an account corresponding to the half-maximal rate, K_ma, (median: 1077 mg, range: 235–4376 mg), time of the absorption cessation, T_abs, (median: 1.72 h, range: 0.82–4.53 h) and absorption lag time, T_lag, (median: 0.085 h, range: 0–0.123 h). It was shown, that the first-order absorption parallel to the saturable process is negligible in the dose range studied. The model described well the dependence of areas under concentration-time curves on the dose determined in several earlier studies. It was used also to predict the fraction of the amoxicillin dose absorbed for different doses. Simulations performed over a wide dose range (50–10000 mg) demonstrated that the fraction absorbed decreases nonlinearly from 90% at 50 mg to 22% at 10000 mg and strongly depends on the duration of the absorption period.