Pharmacokinetic studies of nifedipine tablet. Correlation with antihypertensive effects.

A tablet form of nifedipine was given to eight hypertensive hospitalized men (Stage I or II WHO, 45 +/- 10 years old). After an initial placebo test, 20, 40, and 60 mg of nifedipine were given at 8.00 a.m. in random order at 72-hour intervals in a single administration double-blind crossover study. Blood pressure and heart rate were measured twice by the same observer every 20 minutes from 7.00 a.m. to 8.00 a.m. and then hourly until 8.00 p.m., first with the patients recumbent and again after 1 minute of standing. Plasma nifedipine levels were assayed in samples drawn hourly from 8.00 a.m. to noon, every 2 hours from noon to 8.00 p.m., and at 24 and 48 hours after drug ingestion. The three doses all lowered blood pressure significantly. The reduction during recumbency was significantly larger (-18%) and lasted longer (12 hours) after 60 mg than after 20 mg (-11% at 7 hours). The three doses caused similar increases in heart rate (+29% to +38%), the maximum occurring at the second hour and lasting for 5 hours. The peak plasma concentrations and areas under the plasma concentration time curve were dose-dependent; kinetics were linear between 20 and 60 mg, and the half-life of nifedipine tablets was close to 10 hours. The decrease in mean arterial blood pressure correlated strongly with plasma nifedipine levels (r = 0.61; n = 190; p less than 0.001). Four patients experienced mild side effects (headaches, flushes, drowsiness, or weakness). The tablet form of nifedipine had a potent antihypertensive action that lasted longer than that of the capsule formulation.

Pharmacokinetics of ornidazole in patients with severe liver cirrhosis.

Pharmacokinetics of ornidazole, a nitroimidazole derivative, was studied after intravenous injection in 10 patients with severe alcoholic cirrhosis and 10 healthy volunteers. Plasma concentrations of ornidazole and its two major hydroxylated metabolites, M1 (alpha-(chloromethyl)-2-hydroxymethyl-5-nitroimidazole-1-ethanol) and M4 (3-(2-methyl-5-nitroimidazole 1-yl) 1,2 propane diol), were measured by HPLC. The t1/2 of ornidazole was 14.1 +/- 0.5 hours for normal subjects and 21.9 +/- 2.9 hours for patients with cirrhosis. Mean plasma clearance was 50.6 +/- 2.1 ml/min in control subjects and 34.9 +/- 4.9 ml/min in patients, whereas apparent V SS was not modified in hepatic insufficiency. In healthy volunteers, M1 and M4 levels are well below levels of the parent drug; in cirrhosis both metabolites accumulate in plasma as a result of decreased elimination. Hepatic cirrhosis prolongs ornidazole elimination, and to avoid cumulation the interval between repeated doses could be doubled.

Pharmacokinetics of ornidazole in patients with acute viral hepatitis, alcoholic cirrhosis, and extrahepatic cholestasis.

Pharmacokinetics of ornidazole, a nitroimidazole derivative, was investigated after intravenous injection in 3 groups of 10 patients with different hepatic diseases: hepatitis, noncholestatic cirrhosis and extrahepatic cholestasis. Plasma concentrations of ornidazole and its two major hydroxylated metabolites, M1 [alpha-(chloromethyl)-2-hydroxymethyl-5-nitroimidazole-1-ethanol] and M4 [3-(2-methyl-5-nitroimidazole 1-yl)-1,2-propane diol] were measured by HPLC assay. As a consequence of a decreased clearance (26% to 48%), the half-life and MRT are increased in all patients by 19% to 38% when compared with healthy volunteers. No clear difference could be established between the different groups. The volume of distribution remains the same in all patients and controls except those suffering from cancer. As previously shown in patients with severe liver cirrhosis, both metabolites accumulate in plasma as a result of decreased elimination; formation is no longer the rate-limiting step of their kinetics. This metabolite accumulation is in part due to decreased biliary excretion and to hepatocellular failure.

Moxalactam kinetics during chronic ambulatory peritoneal dialysis.

Moxalactam kinetics in renal failure were followed in eight patients undergoing chronic ambulatory peritoneal dialysis (CAPD) after a single 1-gm IV infusion. Elimination t 1/2 was 16.7 +/- 2.1 hr, with an apparent volume of distribution of 0.21 +/- 0.01 l/kg and plasma clearance of 10.6 +/- 2 ml/min. In 24 hr, 17.4 +/- 3.1% of the dose was present in the dialysis fluids, and 14.6 +/- 5.7% was excreted in the urine. Renal and peritoneal clearance values were thus 2.3 +/- 1.1 and 2.7 +/- 0.5 ml/min. Peritoneal concentrations were high (22.7 +/- 2.2 micrograms/ml). A recommended dosage schedule is proposed on the basis of moxalactam kinetics during CAPD.

Zidovudine disposition in patients with severe renal impairment: influence of hemodialysis.

Pharmacokinetics of zidovudine (azidothymidine, AZT) was investigated after oral administration (200 mg) in 25 HIV seronegative subjects: 14 patients with severe renal impairment (creatinine clearance 6 to 31 ml/min), five hemodialyzed anuric patients, and six healthy subjects. Plasma and urine concentrations of zidovudine and its glucuronidated metabolite (GAZT) were measured simultaneously by HPLC assay. In healthy subjects, GAZT concentrations were higher than those of AZT; AUC values were 23.7 +/- 1.9 and 5.2 +/- 0.6 mumol.hr/L, respectively. Formation of GAZT rate-limits its elimination: GAZT half-life (t 1/2) parallels that of AZT, which is around 1 hour. In uremic patients, AZT concentrations were moderately increased (AUC = 11.7 +/- 1.1 mumol.hr/L), whereas t 1/2 and mean residence time (MRT) remain unchanged despite the decreased renal clearance (16 +/- 2 versus 220 +/- 58 ml/min) and decreased urinary excretion (1.6 +/- 0.3 versus 8.1 +/- 1.0% of the dose). In contrast, GAZT concentrations are markedly increased (AUC = 402.9 +/- 88.6 mumol.hr/L). As a consequence of the decreased renal clearance (27 +/- 3 versus 331 +/- 42 ml/min), elimination is the rate-limiting step and t 1/2 is increased (8 +/- 2 versus 0.9 +/- 0.1 hr). Contribution of a 4-hour hemodialysis session to AZT elimination appears to be negligible, whereas elimination of GAZT is enhanced. On the sole basis of AZT pharmacokinetic data, no particular dose adjustment appears to be necessary in patients who have severe renal impairment (creatinine clearance between 10 and 30 ml/min). However, high levels of GAZT should be anticipated with the usual dosage regimen.

Pharmacokinetics of zidovudine in patients with liver cirrhosis.

The pharmacokinetics of zidovudine (azidothymidine, AZT) was investigated after oral administration (200 mg) in 14 human immunodeficiency virus seronegative patients with liver cirrhosis. They were divided in three groups according to the severity of the liver disease quantitated by the Child-Pugh score. Plasma and urine concentrations of zidovudine and its glucuronidated metabolite (GAZT) were measured simultaneously by HPLC assay. Findings were compared with those previously measured in six healthy volunteers. As a consequence of a marked drop in oral clearance (10 +/- 4 versus 38 +/- 15 ml/min/kg), zidovudine concentrations, half-life, and mean residence time were increased in patients with cirrhosis. No difference could be established between the three groups. The reason for such a decrease in oral clearance of zidovudine was the reduction in the GAZT formation clearance (236 +/- 73 versus 1540 +/- 540 ml/min); this led to a decrease in the AUC ratio of GAZT and zidovudine (1.3 +/- 0.6 versus 4.6 +/- 0.7), which was directly related to the severity of the cirrhosis. In patients, as in volunteers, formation of GAZT rate limits its elimination. To avoid important cumulation of zidovudine after repeated dosing in patients with acquired immunodeficiency syndrome who have hepatic impairment, a dosage adjustment could be proposed.

Pharmacokinetics of newer drugs in patients with renal impairment (Part I).

Many drugs are eliminated via the renal route and the usual dose must be modified in patients with severe renal impairment. This review is an attempt to supply physicians with the more recent data on pharmacokinetic studies of new drugs administered in uraemic patients. The review is in 2 parts: the first indicates the results of studies on the pharmacokinetics of antibiotic agents, antifungal, antiviral and antiulcer drugs, and nonsteroidal anti-inflammatory drugs. Special mention is made of epoetin (recombinant human erythropoietin). It was not possible to give all the information collected from the recent literature: since mild renal failure has little effect on the fate of a drug, pharmacokinetic data obtained in patients with a creatinine clearance (CLCR) of more than 50 ml/min has been omitted. Both the text and tables give recommendations for treating patients with moderate renal insufficiency (CLCR of about 50 ml/min), more severe renal impairment (CLCR between 10 and 50 ml/min) and end-stage renal failure with a very low creatinine clearance (below 10 ml/min). It was not possible to give uniform recommendations (i.e. reducing the dose while maintaining the same interval, or giving the same dose and prolonging the interval). This article follows the recommendations of the authors, which may vary for drugs in similar classes.

Pharmacokinetics of newer drugs in patients with renal impairment (Part II).

Cardiovascular diseases occur frequently in patients with renal failure. Any pharmacokinetic impairment in these diseases should be considered when individualizing drug therapy. The pharmacokinetics of new cardiovascular drugs in uraemic patients are reviewed: alpha- and beta-blocking agents, ACE inhibitors, centrally acting antihypertensive agents, calcium antagonists, antiarrhythmic agents and inotropic agents. Guidelines are proposed for adjustment of dosage regimens as a function of renal impairment. Renal or extrarenal elimination of drugs and their metabolites, and the activity of the latter, are taken into account. The disposition of new drugs such as flestolol, alacepril, delapril, propafenone, milrinone or enoximone, is not well documented in patients with renal failure. Further characterizations of the elimination of these compounds are needed and the potential therapeutic or toxic effects of the metabolites require evaluation to determine whether the dosage needs to be adjusted. Until such investigations are performed, those drugs should not be used in uraemic patients; if no therapeutic alternative is available, clinical controls are necessary at regular intervals. Relationships between pharmacological or therapeutic effects and drug plasma concentrations should be evaluated for such long term use drugs. The knowledge of a plasma concentration therapeutic window is important to provide information which will be useful in determining appropriate drug dosage in renal failure.

Drug interactions with antiviral drugs.

Antiviral drug interactions are a particular problem among immuno-compromised patients because these patients are often receiving multiple different drugs, i.e. antiretroviral drugs and drugs effective against herpesvirus. The combination of zidovudine and other antiretroviral drugs with different adverse event profiles, such as didanosine, zalcitabine and lamivudine, appears to be well tolerated and no relevant pharmacokinetic interactions have been detected. The adverse effects of didanosine and zalcitabine (i.e. peripheral neuropathy and pancreatitis) should be taken into account when administering these drugs with other drugs with the same tolerability profile. Coadministration of zidovudine and ganciclovir should be avoided because of the high rate of haematological intolerance. In contrast, zidovudine and foscarnet have synergistic effect and no pharmacokinetic interaction has been detected. No major change in zidovudine pharmacokinetics was seen when the drug was combined with aciclovir, famciclovir or interferons. However, concomitant use of zidovudine and ribavirin is not advised. Although no pharmacokinetic interaction was documented when didanosine was first administered with intravenous ganciclovir, recent studies have shown that concentration of didanosine are increased by 50% or more when coadministered with intravenous or oral ganciclovir. The mechanism of this interaction has not been elucidated. Lack of pharmacokinetic interaction was demonstrated between foscarnet and didanosine or ganciclovir. Clinical trials have shown that zidovudine can be administered safely with paracetamol (acetaminophen), nonsteroidal anti-inflammatory drugs, oxazepam or codeine. Inhibition of zidovudine glucuronidation has been demonstrated with fluconazole, atovaquone, valproic acid (valproate sodium), methadone, probenecid and inosine pranobex; however, the clinical consequences of this have not been fully investigated. No interaction has been demonstrated with didanosine per se but care should be taken of interaction with the high pH buffer included in the tablet formulation. Drugs that need an acidic pH for absorption (ketoconazole, itraconazole but not fluconazole, dapsone, pyrimethamine) or those that can be chelated by the ions of the buffer (quinolones and tetracyclines) should be administered 2 hours before or 6 hours after didanosine. Very few interaction studies have been undertaken with other antiviral drugs. Coadministration of zalcitabine with the antacid 'Maalox' results in a reduction of its absorption. Dapsone does not influence the disposition of zalcitabine. Cotrimoxazole (trimethoprim-sulfamethoxazole) causes an increase in lamivudine concentrations by 43%. Saquinavir, delavirdine and atevirdine appeared to be metabolised by cytochrome P450 and interactions with enzyme inducers or inhibitors could be anticipated. Some studies showed that interferons can reduce drug metabolism but only a few studies have evaluated the pathways involved. Further studies are required to better understand the clinical consequences of drug interactions with antiviral drugs. Drug-drug interactions should be considered in addition to individual drug clinical benefits and safety profiles.

Disposition of fleroxacin, a new trifluoroquinolone, and its metabolites. Pharmacokinetics in elderly patients.

The pharmacokinetics of fleroxacin and its main metabolites, N-demethyl-fleroxacin and N-oxide-fleroxacin, were studied in 12 elderly patients aged 63 to 88 years. Plasma and urine samples collected at different times after drug administration were analysed by a specific reverse phase high performance liquid chromatography (HPLC) method. The peak plasma concentration (Cmax) of fleroxacin was 15.6 +/- 1.6 mg/L, time to Cmax (tmax) was about 3h, elimination half-life (t1/2) was 16 +/- 1h and the percentage of unchanged fleroxacin excreted in urine was 39 +/- 3% of the dose. The plasma concentrations of metabolites were very low and accounted for no more than 4% of the concentration of unchanged fleroxacin. Plasma parameters were mainly correlated with age and weight; urinary parameters were correlated with creatinine clearance. Compared with results in younger normal patients, no significant change in the t1/2 of fleroxacin or metabolites was observed. Assuming that the bioavailability (f) is complete, the apparent volume of distribution (Vd/f) was lower in elderly (0.9 +/- 0.1 L/kg) than in younger patients (1.3 +/- 0.1 L/kg) and a 2-fold decrease in apparent total clearance (CL/f) was noted (2.58 +/- 0.42 vs 4.86 +/- 0.72 L/h); plasma concentrations were consequently higher in elderly patients. Compared with patients with renal failure, the pharmacokinetics of fleroxacin and metabolites in the elderly were similar to those of patients with mild to moderate renal insufficiency. On the basis of the findings of this single dose study, no major dosage adjustments are needed for patients of this age range except for those with creatinine clearance less than 30 ml/min.

Disposition of fleroxacin, a new trifluoroquinolone, and its metabolites. Pharmacokinetics in renal failure and influence of haemodialysis.

The pharmacokinetics of fleroxacin and its metabolites following a single oral dose of fleroxacin 400mg were examined in 6 healthy subjects and 24 patients with various degrees of renal insufficiency. Plasma and urine samples, collected at various times after administration, were assayed by high performance liquid chromatography (HPLC). In healthy subjects, Cmax was 6.8 +/- 0.7 mg/L; tmax = about 1h, t1/2 = 14 +/- 2h, total clearance = 4.86 +/- 0.72 L/h and the percentage of unchanged fleroxacin excreted in urine in 48 hours was 48 +/- 4% (HPLC). Plasma concentrations of metabolites were very low and accounted for no more than 5% of the levels of unchanged fleroxacin. In uraemic patients Cmax did not change, whatever the degree of renal failure; tmax was increased in patients with a glomerular filtration rate below 0.6 L/h, and Vd/f was independent of the severity of renal failure. These data suggest that bioavailability of the drug is unchanged. In uraemic patients t1/2 was prolonged and AUC multiplied by a factor of 2 to 3. A linear relationship was found between total and renal clearances of fleroxacin and creatinine clearance. Accumulation of N-demethyl-fleroxacin and N-oxide-fleroxacin was very high in uraemic patients, due to slow formation of these metabolites and decreased urinary elimination. Dialysance of fleroxacin and of its metabolites was approximately 3.6 to 4.8 L/h. These findings suggest that fleroxacin dosage may need to be reduced in patients with severe renal disease; in haemodialysed patients, treated every 2 days, a single dose of fleroxacin 400mg is recommended at the end of each dialysis session.

Pharmacokinetics of rilmenidine.

Rilmenidine, an alpha 2-adrenoceptor agonist, was studied (1 mg single dose) in order to determine the effects of pathology on its basic pharmacokinetic parameters. Because of the mainly renal elimination of rilmenidine, studies involved hypertensive, elderly hypertensive, renal insufficient and hepatic insufficient patients. Hypertension was found to influence neither the absorption, the distribution nor the elimination processes; the linearity in the range of 1 to 2 mg and the absence of accumulation in long-term treatment were confirmed. In contrast, in the elderly, the absorption phase was delayed. The slight decrease in the apparent volume of distribution (-12%), with a notable decrease in the apparent total clearance (-50%) led to a prolonged elimination half-life (+50%). In renal failure, linear relations between the degree of renal impairment and the elimination parameters were shown. These relations allow the evaluation of the predicted steady-state level of rilmenidine for a given degree of renal failure. In hepatic insufficiency, the modification of rilmenidine disposition concerned exclusively the elimination phase in which apparent clearance was decreased approximately 20%. In conclusion, these results lead to a decreased dosage regimen in patients with severe renal failure.

Lack of interaction between nizatidine and warfarin during chronic administration.

Nizatidine is a new antagonist of H2 receptors. The nizatidine warfarin interaction was investigated in healthy volunteers during chronic warfarin (mean warfarin dose: 5 +/- 0.9 mg/d) and nizatidine (300 mg/d) administration. Nizatidine coadministration did not increase the prothrombin time, kaolin-cephalin clotting time, and did not modify the activity of clotting factors II, VII, IX, X. Nizatidine did not influence the steady-state plasma warfarin concentration.

Do we need highly sensitive analytical techniques in phase I?

Pharmacokinetic studies constitute part of phase I clinical trials. Initiation of dosage regimen in phase II and III clinical trials depends on drug pharmacokinetics and the choice of dosing interval relies on the elimination rate constant. Consequently, inaccurate determination of these parameters can lead to unexpected drug levels and side-effects in patients and can delay the clinical development of the drug.

Human pharmacokinetics of a perfluorocarbon ultrasound contrast agent evaluated with gas chromatography.

The purpose of this study was to prospectively study the human pharmacokinetics of an ultrasound (US) contrast agent through its active ingredient, dodecafluoropentane (DDFP). Expired air and blood samples were collected from 24 volunteers after IV administration from 0.01 to 0.1 mL/kg. They were analyzed by a gas chromatographic method specially adapted to the study of DDFP. Blood data fitted to an open one-compartment model. Elimination half-life range was 1.8 to 2.5 min. The area under the curve was correlated to the dose (r(2) = 0.99). Mean blood clearance ranged from 30 to 49 mL/min kg. Blood apparent distribution volume ranged from 0.09 to 0.15 L/kg. In expired air, DDFP concentration exhibited a biexponential decay. The percentage of recovery was 98 +/- 19% at 2 h. No extraneous peaks were observed, indicating no detectable DDFP metabolites. It was concluded that DDFP pharmacokinetics in blood fitted to an open one-compartment model with a fast elimination half-life. Recovery in expired air was almost complete 2 h after administration.

Cimetidine does not alter sparfloxacin pharmacokinetics.

The interaction between cimetidine and sparfloxacin was studied in 10 healthy volunteers who received a single oral dose of 400 mg sparfloxacin on the third day of an 8 day cimetidine (400 mg t.i.d.) or placebo randomly assigned treatment. No statistically significant differences were observed in the pharmacokinetic parameters (Cmax-AUC-T1/2-urinary excretion and metabolic ratio) of sparfloxacin following the 2 treatment. Cimetidine does not affect absorption, metabolism or urinary excretion of sparfloxacin; consequently, patients exposed to this drug combination are not at risk.

Placental passage of azathiothymidine (AZT) during the second trimester of pregnancy: study by direct fetal blood sampling under ultrasound.

AZT-therapy during pregnancy is actually contraindicated. Two HIV-positive pregnant women who were due to have an induced abortion in the second trimester of pregnancy, were treated with AZT. Blood samples from mothers and fetuses and amniotic fluid samples were taken simultaneously. AZT crossed the placental barrier in the two patients. AZT and GAZT concentrations from the two fetuses were close to those obtained in the two women and in six non-pregnant volunteers.

Pharmacokinetics of lamotrigine in patients with renal impairment: influence of haemodialysis.

The pharmacokinetics of a single 100 mg oral dose of lamotrigine, a new anticonvulsant drug, were studied in six healthy volunteers and in twenty patients with various degrees of renal impairment. Six of these patients were regularly haemodialysed. Lamotrigine concentrations in plasma and urine were measured by the HPLC method. The mean peak plasma concentrations of lamotrigine, tmax, volume of distribution and total clearance were not significantly modified by the degree of renal impairment. The elimination half-life of lamotrigine was approximately 25 h in subjects with normal renal function and 50 h in uraemic patients. These are very large variations in uraemic patients and the results were not statistically significant. Renal clearance of lamotrigine is significantly reduced. Urinary elimination of unchanged and conjugated lamotrigine was reduced in uraemic patients. Thus it seems necessary to treat carefully patients with a very severe renal insufficiency since very large variations in pharmacokinetics were found. A 100 mg oral dose every two days is recommended if creatinine clearance is below 10 ml/min. Haemodialysis shortened the elimination half-life from 59.6 +/- 28.1 h during the interdialysis period to 12.2 +/- 6.4 h during the dialysis period; 17% of the dose was extracted by haemodialysis.

[Clinical pharmacology of calcium inhibitors]. / Pharmacocinétique clinique des inhibiteurs calciques.

The pharmacokinetics of the commercially available calcium antagonists, diltiazem (Tildiem), nifedipine (Adalate), perhexiline (Pexid), and verapamil (Isoptine) are well known; the pharmacokinetics of bepridil (Cordium) need further study. The properties of nicarpidine, a molecule currently being tested, will also be described. These products are well absorbed from the gastrointestinal tract but undergo variable degrees of transformation during the first passage through the liver. The bioavailabilities of bepridil, diltiazem and nifedipine are of the order of 40 to 60%; those of verapamil and nicarpidine are lower, 10-20% and 15-30%, respectively. The rates of absorption vary according to the derivatives and galenic preparations; in general, they are rapid; peak plasma concentrations are usually obtained one to four hours after administration. Protein binding is high but does not interfere in the distribution; the volumes of distribution of bepridil, diltiazem and verapamil are large (4-5 l/kg); those of nifedipine and nicardipine are smaller (l l/kg). The halflives of diltiazem, nifedipine, nicardipine and verapamil are short (1 to 5 hours); those of bepridil and perhexiline are longer (2 to 3 days). The main method of elimination is by hepatic transformation with high plasma clearance rates: diltiazem and verapamil have pharmacologically active derivatives whose contributions to the overall activities of the drugs are not fully understood. Physiopathological changes of the pharmacokinetic properties of diltiazem and verapamil (elderly patients, hepatic failure) have been described.

[Neurological disorders and perhexiline maleate therapy. Clinical study of 10 cases. Neuropathological, pharmacocinetic and biochemical studies (author's transl)]. / Manifestations neurologiques en rapport avec le traitement par le maléate de perhexiline. Etude clinique d'une série de 10 cas. Documents neuropathologiques, pharmacocinétiques et biochimiques.

Ten new cases of perhexiline induced peripheral neuropathies are reported. The authors emphasize the possible association of other neurological disorders: cerebellar symptoms in one case, complex tremor in two other cases, marked decrease of photomotor reflexes in one case and disgeusia in another one. The pharmacocinetic study of 4 cases revealed the presence of a low metabolism of the drug in one of them. Polymorphous inclusions have been seen in Schwann cell and endothelial cell cytoplasm in the three patients with electron microscopic study of the nerves. The pathological study of one case showed the demyelination of spinal cord posterior columns. In another case, who died from hepatic coma, the biochemical study of cerebral lipids revealed the low values of cerebrosides and sulfatides in cerebellum and cerebral white matter.