Age and ceftriaxone kinetics.

One gram ceftriaxone was injected at a constant rate in an intravenous infusion over 30 min to eight elderly subjects (mean age, 70.5 yr) and eight young subjects (mean age, 28.9 yr); the latter served as body weight-matched controls. Plasma and urine samples were collected in serial order for 48 hr and assayed for unchanged drug. Selected plasma samples were subjected to protein binding determinations by equilibrium dialysis. Statistical comparison of data for the old and young indicated no significant changes in means of (1) maximum plasma concentration (140 and 133 micrograms/ml); (2) elimination rate constant (0.078 and 0.093 hr-1) and elimination t1/2 (8.9 and 7.5 hr); (3) apparent volume of distribution (10.69 and 11.01 l); (4) plasma clearance (833 and 1023 ml/hr); (5) nonrenal clearance (515 and 606 ml/hr); and (6) percent dose excreted unchanged in urine (39.6 and 41.4). There was, however, a significant decrease in the renal clearance (318 and 416 ml/hr) and a significant increase in the plasma free fractions (0.157 and 0.136 at 100 micrograms/ml and 0.146 and 0.114 at 60 to 70 micrograms/ml) of ceftriaxone in elderly subjects. The 24% decrease in renal clearance in the elderly subjects corresponded to the 19% decrease in their creatinine clearance. Since the age-related changes in kinetics were relatively small, it is concluded that dosage adjustment is probably not necessary for elderly subjects requiring ceftriaxone.

Use of an indirect pharmacodynamic stimulation model of MX protein induction to compare in vivo activity of interferon alfa-2a and a polyethylene glycol-modified derivative in healthy subjects.

Interferon alfa-2a was chemically modified by the covalent attachment of a polyethylene glycol (PEG) moiety to enhance its circulating half-life and to reduce its immunogenicity. A comparative evaluation of the pharmacokinetics of the PEG-modified interferon alfa-2a showed a greater than twofold increase in the circulating half-life as a result of this chemical modification. An indirect physiologic response model was developed to characterize the time course of the MX protein response after subcutaneous administration of single ascending doses of either interferon alfa-2a or PEG-interferon alfa-2a in healthy volunteers. Analysis of the pharmacokinetic-pharmacodynamic relationship suggested that the PEG-modified interferon alfa-2a could not be administered less than twice weekly and therefore offered little therapeutic advantage over its unmodified counterpart, which is administered three times weekly. These results were consistent with findings in phase II trials. This study substantiates the usefulness of pharmacodynamic modeling as a tool for the development of dose recommendations and for the early selection of drug candidates in the drug development process.

Phenobarbital--valporic acid interaction.

The effect of subchronic valproate treatment on the single-dose kinetics of phenobarbital was investigated in 6 normal subjects. The study consisted of 2 drug treatments assigned through randomized crossover design. In one treatment subjects received a 60-mg dose of phenobarbital orally. In the other, subjects received 250 mg valproic acid orally twice daily for 14 consecutive days and a 60-mg dose of phenobarbital orally on day 4. Nineteen plasma samples (over 12 days) and two 48-hr urine samples were collected during each treatment. Plasma and urine phenobarbital levels were determined by gas chromatograph interfaced with mass spectrometer in a chemical ionization mode (GLC/CI/MS) and plasma valproic acid levels by GLC. Valproic acid induced several changes in the elimination parameters of phenobarbital: (1) phenobarbital half-life rose from 96 to 142 hr (p = 0.006); (2) plasma clearance fell from 4.2 to 3.0 ml/hr/kg (p = 0.009); (3) renal clearance was unchanged, and metabolic clearance fell from 3.3 to 2.0 mg/hg/kg (p = 0.006); and (4) the fraction of dose excreted unchanged rose from 0.22 to 0.33 (p = 0.015), and the fraction of dose metablized fell from 0.78 to 0.67 (p = 0.015). The findings indicate that valproic acid inhibits phenobarbital metabolism.

Valproic acid dosage and plasma protein binding and clearance.

Valproic acid clearance was determined in six normal subjects during a single-dose (250-mg) study and multiple-dose experiments of 500, 1,000, and 1,500 mg/day. Eight consecutive oral doses were taken at 12-hr intervals at each dosing level. Valproate levels and protein binding were determined at steady state. Clearance declined 20% from 8.33 +/- 2.44 to 6.67 +/- 1.25 ml/hr/kd between the single-dose and the 500-mg/day steps (p = 0.05). Clearance was unchanged between the 500- and 1,000-mg/day steps despite a 44% increase in mean free fraction (0.0703 +/- 0.0381 vs 0.1011 +/- 0.0438, p < 0.05), implying a balanced opposing decline in intrinsic clearance (from 89.2 +/0 71.0 to 72.0 +/- 20.8 ml/hr/kg; p = 0.025). In four subjects completing the 1,500-mg/day step, clearance increased from 6.76 +/- 1.48 ml/hr/kg (1,000- mg/day) to 8.20 +/- 1.62 ml/hr/kg, corresponding to a further increase in free fraction. Free fraction varied within a single dosing interval (%SD = 11% to 49%). The apparent dose-related decline in intrinsic clearance suggests autoinhibition or saturation of metabolism.

Simultaneous modeling of the pharmacokinetics and pharmacodynamics of midazolam and diazepam.

The pharmacokinetics and pharmacodynamics of midazolam and diazepam were compared after intravenous infusions of 0.03 and 0.07 mg/kg midazolam and 0.1 and 0.2 mg/kg diazepam on four separate occasions in 12 healthy male subjects in a randomized four-way crossover design. The Digit Symbol Substitution Test (DSST) was used as a measure of drug effect. Subjects performed three practice tests before dosing to account for any effects caused by familiarization ("learning curve") with the testing procedure. Pharmacokinetic and pharmacodynamic data were simultaneously fitted to a semiparametric model. In this model, a pharmacokinetic model related dose to plasma concentrations, a link model related plasma concentrations to the concentration at the effect site, and a pharmacodynamic model related the effect site concentration to the observed effect. The plasma-effect site equilibrium half-life was approximately 2 1/2 times longer for midazolam than for diazepam, which is in good agreement with previously published data. Based on the estimated effect site concentration at which half of the maximal effect was reached, midazolam had approximately a sixfold greater intrinsic potency than diazepam. This difference in potency was also observed in a previous study that used transformed electroencephalographic (EEG) data to assess pharmacodynamic activity. The findings reported here with a clinically relevant pharmacodynamic marker (DSST) confirm the utility of surrogate drug effect measures such as EEG. This work also shows the feasibility of conducting pharmacokinetic pharmacodynamic analysis during the drug development process.

Retrospective population-based analysis of the dose-response (fecal fat excretion) relationship of orlistat in normal and obese volunteers.

Orlistat, an inhibitor of gastrointestinal lipases, limits the absorption of ingested fat and could become a potential treatment for obesity. This analysis was performed to elucidate the relationship between orlistat dose and intensity of inhibition of dietary fat absorption (assessed by measuring fecal fat excretion). In 11 phase I double-blind, placebo-controlled, parallel-group randomized studies, a total of 171 subjects received oral daily doses that ranged from 30 to 1200 mg orlistat or matching placebo three times a day for 9 to 10 days. The results of the daily mean fecal fat excretion percentage (relative to ingested fat) were correlated to the orlistat daily dose. A simple maximum-effect model that included a basal value was used to fit the dose-response relationship for all evaluable subjects. The mean maximum percentage of ingested fat excreted in the feces was approximately 32% during orlistat administration compared with 5% during placebo administration. The orlistat daily dose that produced 50% of the maximum effect was 98 mg/day. The model-fitting suggests the existence of a steep portion of the dose-response curve up to approximately 400 mg/day, with a subsequent tendency to plateau at higher doses. Such an analysis was instrumental in identifying appropriate doses to be used in therapeutic trials for weight loss in obese patients.

The pharmacokinetic-pharmacodynamic (Digit Symbol Substitution Test) relationship of flumazenil in a midazolam steady-state model in healthy volunteers.

To characterize the plasma concentration-effect relationship of flumazenil in the presence of a predefined midazolam level, a double-blind, placebo-controlled, randomized two-way crossover study was conducted in nine healthy male subjects. After reaching a criterion level of midazolam-induced depression of the Digit Symbol Substitution Test (DSST), volunteers received a dose of flumazenil (1.0 mg) or placebo over 1 minute, with the infusion of midazolam continued. Blood samples were collected, simultaneously with the DSST assessment, at predetermined intervals and were assayed for flumazenil and/or midazolam plasma concentrations. Pharmacokinetic-pharmacodynamic modeling techniques were used to estimate the equilibration rate constant (keo) between plasma concentration and effect for flumazenil; a sigmoidal maximum-effect model was used to relate the DSST score to the flumazenil plasma concentration. Flumazenil exhibited a rapid onset (the half-life of equilibration between drug concentration in the blood and drug effect was 3.3 minutes) and short duration of action (the flumazenil plasma concentration causing half-maximal effect was 7.4 ng/ml, which was reached about 1 hour after dosing). The results of this study also show the competitive nature of flumazenil as a midazolam antagonist.

Pharmacokinetic profile of ceftriaxone in man.

In human subjects, ceftriaxone exhibits an exceptionally long elimination half-life (5.8 to 8.7 hours) and a small degree of nonlinearity in its pharmacokinetics which can be ignored in its clinical applications. Thirty-three to 67 percent of a dose is excreted in the urine as unchanged drug, and the remainder is secreted in the bile and ultimately is found in the feces as microbiologically inactive compounds. Ceftriaxone is rapidly and completely absorbed following intramuscular administration. Multiple dosing of ceftriaxone with doses ranging from 0.5 to 2 g at 12- or 24-hour intervals by intravenous and intramuscular routes resulted in 15 to 36 percent accumulation of ceftriaxone in plasma and no change in its elimination half-life. The volume of distribution and the plasma clearance of ceftriaxone in pediatric patients were threefold greater than those in adults, and ceftriaxone penetrated the inflamed meninges of infants and children with bacterial meningitis. Small changes in the pharmacokinetics of ceftriaxone in elderly subjects or patients with renal or hepatic dysfunction are such that dose adjustments should not be necessary with a ceftriaxone dosage up to 2 g per day. Ceftriaxone was not removed to any significant extent from plasma by hemodialysis. In a small percentage of patients, on dialysis, the elimination rate of ceftriaxone was significantly reduced, suggesting that plasma concentrations of ceftriaxone should be monitored in these patients to determine if dosage adjustments are necessary.

An evaluation of the integration of pharmacokinetic and pharmacodynamic principles in clinical drug development. Experience within Hoffmann La Roche.

The integration of pharmacokinetic and pharmacodynamic principles into drug development has been proposed as a way of making it more rational and efficient. The use of these principles in drug development to make scientific and strategic decisions is defined as the 'pharmacokinetic-pharmacodynamic guided approach to drug development'. The objectives of this survey were: (i) to assess the extent the pharmacokinetic-pharmacodynamic guided approach to drug development has been used in a large multinational pharmaceutical company: (ii) to evaluate the impact of pharmacokinetic and/or pharmacodynamic results on clinical drug development; and (iii) to identify factors which prevented the full application of the pharmacokinetic-pharmacodynamic guided approach. This was done by looking at 18 projects in the current development portfolio at Hoffman La Roche and evaluating the use of this approach by interviewing the responsible clinical pharmacologist using a standardised questionnaire. (i) Benefits from using the pharmacokinetic-pharmacodynamic guided approach were reported in every project, independent of development phase and therapeutic area. This approach was more extensively used in the recent projects. The selection of dosages in clinical studies was found to be the most important application of pharmacokinetic-pharmacodynamic results in terms of an impact on drug development. (ii) Time savings, up to several months, could be quantified in 8 projects during the entry-into-man studies and in 6 projects during the phase II or III studies. In 4 projects, 1 clinical study was avoided. (iii) The most important scientific factor preventing the full application of the approach was the lack of knowledge on the predictive value of the pharmacodynamic or surrogate marker for effect (6 projects). The results of the survey have shown that the use of the pharmacokinetic-pharmacodynamic guided approach has contributed to making clinical drug development more rational and more efficient. Opportunities to apply the pharmacokinetic-pharmacodynamic approach should be identified in each project and a project specific strategy for the pharmacokinetic-pharmacodynamic guided approach should be defined during phase 0 of drug development.

Effects of age, gender and oral contraceptives on intramuscular midazolam pharmacokinetics.

The effects of age, gender and low-dose (50 mcg or less) oral contraceptive steroids (OCS) on the pharmacokinetics of midazolam were evaluated following a single 7.5 mg intramuscular dose to five groups (8/group) of healthy volunteers consisting of young males, young females, elderly males, elderly females, and young female users of oral contraceptives. Blood samples were collected at specified times over a 24-hour period, and plasma concentrations of midazolam and its 1-hydroxymethyl metabolite were determined by a GC-EC assay. Midazolam was rapidly absorbed following intramuscular administration to the different groups. Comparison of young men vs elderly men, young women vs elderly women, young men vs young women, elderly men vs elderly women, and young women OCS-users vs young women non-OCS users indicated no substantial differences in the pharmacokinetic profile of midazolam between groups except for the comparison between the young and elderly men groups. The rate of elimination of midazolam was significantly slower in the elderly males compared to the young men. The pharmacokinetic profile of 1-hydroxymethyl midazolam paralleled that of the parent compound. This is to be expected since this metabolite exhibits formation rate-limited kinetics. Except for one subject who reported hives and itching, considered to be remotely related to test drug, no other adverse experiences or laboratory abnormalities were reported.

Influence of food on midazolam absorption.

The influence of food on the absorption of midazolam, a new benzodiazepine derivative, was investigated in 18 healthy volunteers in a four-way, randomized, crossover study with a one-week washout period between treatments. Single 15-mg oral doses of midazolam were administered one hour before, with, and one hour after a standard meal as well as under fasting conditions (control). Following serial blood sampling over the next 24-hour period, midazolam plasma concentrations were determined by gas chromatography and mass spectrometry for pharmacokinetic evaluation. The maximum plasma concentration (Cmax), time of maximum concentration (tmax), lag time prior to absorption (tlag), area under the plasma concentration-time curve (AUC), and elimination rate constant of midazolam and 1-hydroxymethylmidazolam were determined. Significant changes in these parameters were not found when midazolam was taken one hour before or with a meal as compared with the control condition. Significant changes in the Cmax, tmax, and AUC parameters for both midazolam and its metabolite were seen when midazolam was ingested one hour after a meal: There was a delayed and reduced rate of absorption as well as a small reduction in the extent of absorption. Thus, ingestion of midazolam within one hour after a meal may result in a delay in the onset of the pharmacologic effect. These changes may be of some clinical significance in that they may potentially delay the onset of sleep.

Review of limited systemic absorption of orlistat, a lipase inhibitor, in healthy human volunteers.

Orlistat, a lipase inhibitor, acts locally in the gastrointestinal tract. Systemic absorption is not required for its efficacy, but knowledge of the extent of its systemic absorption is important for its safe use in obese patients, the intended target population. Pharmacokinetic screening was carried out by monitoring plasma concentrations of unchanged orlistat in 25 phase 1 studies (including two mass balance studies) in normal and obese healthy volunteers. The results of these studies indicate an extremely low degree of systemic absorption for orlistat when administered with a hypocaloric, well-balanced diet with 20% to 30% of calories derived from fat (50-80 gm). To further characterize the pharmacokinetics and excretion pathways of orlistat, two mass balance studies using 14C-labeled orlistat were conducted. After oral dosing of radiolabeled orlistat with a fatty meal (28-30 gm fat), almost the entire dose was recovered from fecal samples; little was found in plasma and urine. It is concluded that systemic absorption of orlistat is negligible; at a clinically efficacious dose level, orlistat is unlikely to produce systemic lipase inhibition.

The effect of orlistat, an inhibitor of dietary fat absorption, on the pharmacokinetics of beta-carotene in healthy volunteers.

To assess the influence of orlistat, a lipase inhibitor, on the absorption of beta-carotene, an open-label, parallel, placebo-controlled, randomized, two-way crossover study was performed in 48 healthy volunteers between the ages of 19 and 58 years. Each subject received a single oral dose of 0, 30, 60, or 120 mg beta-carotene (12 subjects per dose level) on the fourth day of treatment with orlistat (120 mg) or placebo 3 times a day for 6 days. The treatments were separated by a washout period of at least 5 weeks. Serial blood samples were collected before and at appropriate intervals after administration of beta-carotene to determine plasma concentrations of unchanged beta-carotene. Short-term (3 to 6 days) treatment with orlistat did not alter endogenous profiles of beta-carotene in plasma. When beta-carotene was given during orlistat treatment, its absorption was reduced by approximately one-third. This reduction was consistent for all three dose levels of beta-carotene studied; however, the results for the 30-mg dose level were subject to greater variability, particularly for area under the concentration-time curve (AUC). It was concluded that two thirds of a supplemental dose of beta-carotene will be absorbed during orlistat treatment; this may be sufficient to achieve physiologic levels of beta-carotene with an appropriate dose of beta-carotene, should supplementation be needed in obese patients who have developed beta-carotene deficiency during therapy with orlistat.

The influence of orlistat on the pharmacokinetics and pharmacodynamics of glyburide in healthy volunteers.

To assess the influence of orlistat on the pharmacokinetics and pharmacodynamics (the blood glucose-lowering effect) of glyburide, an open-label, placebo-controlled, randomized, two-way crossover study was done in 12 healthy male volunteers. Each subject received single 5-mg oral doses of glyburide (Micronase; The Upjohn Company, Kalamazoo, MI) on the fifth day of treatment with placebo (treatment A) and 80-mg orlistat (treatment B) three times a day for 4 1/3 days; the two treatments were separated by a five-day washout period. Serial blood samples were collected before and at appropriate intervals after each glyburide dose to determine plasma concentrations and blood glucose levels. Values of Cmax and AUC of glyburide showed an equality of the two treatments by the analysis of variance. There was an apparent correlation between blood glucose level and the logarithm of plasma glyburide concentration; this relationship appeared to not be altered when glyburide was administered with orlistat. In conclusion, orlistat administered at doses of 80-mg three times daily does not significantly alter the pharmacokinetics and blood glucose-lowering effect of a single 5-mg oral dose of glyburide in healthy volunteers.

Negligible systemic absorption of topical isotretinoin cream: implications for teratogenicity.

The objective of the study was to assess the extent of systemic exposure of retinoic acid metabolites after excessive application of 0.1% isotretinoin cream in patients with photodamaged skin. This was a single-center, open-label, noncomparative, multiple-dose study of isotretinoin cream. Eighteen female patients with photodamaged skin received a 10 g topical application of isotretinoin cream once daily to a surface area of approximately 2,300 cm2 for 42 days. The patients were not allowed to have high vitamin A-containing foods, vitamin A supplements, or concomitant medications during the entire study period. Plasma levels of four retinoic acids (isotretinoin, tretinoin, 4-oxo-isotretinoin, and 4-oxo-tretinoin) were evaluated after 42 days of isotretinoin application and compared with baseline (pretreatment) levels. The mean area under the curve (AUC) in plasma increased by 48% (+/-SE 9.2) and 77% (+/-13) from the 24-hour pretreatment baseline level for isotretinoin and 4-oxo-isotretinoin, respectively, after treatment with excessive amounts of isotretinoin cream, suggesting systemic absorption of isotretinoin cream. This increase in systemic exposure of retinoic acids was less than that reported earlier after the U.S. recommended daily allowance of 5,000 i.u. of vitamin A supplementation (isotretinoin 141 +/- 19% and 4-oxo-isotretinoin 171 +/- 27%). The minimal systemic availability of isotretinoin cream compared with the U.S. recommended daily allowance for vitamin A supplements provides reasonable evidence for lack of its potential teratogenic risk.

Lack of probenecid effect on nonrenal excretion of ceftriaxone in anephric patients.

Probenecid has been shown to decrease renal and biliary excretion of organic acids. In a randomized crossover study, the effect of coadministered probenecid on nonrenal excretion of ceftriaxone was studied in six functionally anephric patients in whom ceftriaxone is eliminated exclusively by nonrenal or presumably by biliary excretion. Each patient received 0.5 g IV ceftriaxone without and with probenecid (0.5 g at 10 and 2 hours prior to ceftriaxone and 0.5 g q12h X 3 doses post ceftriaxone). Serial blood samples were collected over 48 hours and plasma analyzed for ceftriaxone by high performance liquid chromatography (HPLC). Pharmacokinetic analysis was based on a model-independent approach. Probenecid did not significantly affect the disposition of ceftriaxone in this study, thus suggesting that nonrenal excretion of ceftriaxone is not inhibited by probenecid.

Time-dependent kinetics II: Diurnal oscillations in steady-state plasma ethosuximide levels in rhesus monkeys.

Morning steady-state (9 am) plasma levels were significantly higher than the corresponding evening (5 pm) plasma levels during a 3-week zero-order infusion of ethosuximide to six monkeys. These differences could not be explained by experimental variables such as GLC assay and infusion pump. Circadian periodicity in steady-state plasma levels was investigated in three monkeys over 4 months under controlled experimental conditions: blood sampling at 2-hr intervals for 26 hr, 1 day/week; fixed lighting, feeding, and noise schedules; and electroencephalogram monitoring. The plasma concentration-time curves showed two minima in the 12 noon-2 pm and 8 pm-12 midnight periods, and the later involved the largest percent change in plasma levels (4-8%). The plasma concentration-time data were subjected to cross-correlation analysis, which indicated a circadian rhythm in steady-state plasma levels with a period of 24-26 hr.

Synthesis and mechanisms of decomposition of some cephalosporin prodrugs.

The delta-3 and delta-2 methyl esters of cefazolin were synthesized. The kinetics and mechanisms of degradation of the methyl esters and the delta-3 and delta-2 isomers of pivaloyloxymethyl prodrug esters of the new cephalosporin ceftetrame (Ro 19-5247) were investigated in buffer systems and in human plasma in vitro. The major hydrolytic products of all the delta-3 and delta-2 esters were the inactive delta-2 cephalosporin free acids. The following reaction scheme describes the in vitro hydrolysis of these compounds: [formula: see text]. In addition, there was evidence of opening of the beta-lactam ring to form cephalosporoic acid when the methyl ester of cefazolin was studied in human plasma and in the presence of penicillinase. For the methyl esters, the processes represented by k12, k21, and k20 were operative in buffers; in human plasma, the processes represented by k12, k21, and k20 were operative in addition to cephalosporoic acid formation. For the isomers of the cephalosporin prodrug ester Ro 19-5248 only k12 and k20 were operative in buffers; in human plasma all pathways were operative and there was no evidence of cephalosporoic acid formation. In all cases, the processes represented by k12, k21, and k20 were subject to general and/or specific base catalysis.

Time-dependent kinetics III: diurnal oscillations in steady-state plasma valproic acid levels in rhesus monkeys.

Valproic acid was administered by constant rate intravenous infusion to catheterized chained rhesus monkeys for 8-10 weeks under controlled environmental conditions. Steady-state plasma levels were monitored at 2-hr intervals for 26 hr (10 am-12 noon on the following day), 1 day/week for 6 weeks. Individual steady-state plasma concentration-time plots exhibited the following characteristics. During Period A (10 am-6 pm), plasma levels remained stable or decreased. During Period B (6 pm-6 am), plasma levels increased, reached a maximum, and remained markedly higher than during Period A. The maximum concentrations were 40-140% higher than the observed minimum concentrations. During Period C (6 am-noon), plasma levels tended to decline from the maximum concentrations achieved in Period B. In most cases, plasma concentrations at 10 am and 12 noon of the 2nd experimental day fell within 10% of their respective values on the previous day. The mean (+/- SD) periods obtained by cross-correlation analysis of individual plasma concentration-time plots were 30.7 (+/- 3.7) and 22.8 (+/- 3.6) hr for Animals 903 and 923, respectively. The corresponding mean (+/- SD) amplitudes were 27.3 (+/- 12.6) and 17.4 (+/- 2.3)%. A circadian rhythm in total body clearance was hypothesized, and its pharmacokinetic implications are discussed.

Simultaneous analysis of phenobarbital and p-hydroxyphenobarbital in biological fluids by GLC-chemical-ionization mass spectrometry.

A sensitive and specific GLC-chemical-ionization mass spectrometric method was developed for the simultaneous assay of phenobarbital (I) and p-hydroxyphenobarbital (II) in biological fluids (urine and plasma) using stable isotope analogs of the compounds as internal standards. After extraction, the compounds were methylated with diazomethane and quantitated by GLC-chemical-ionization mass spectrometry. The detection limit of the method was 0.1 micrograms/ml for both compounds. The intraday precision (RSD) for 0.4-2.4 micrograms/ml was < 2% for I and < 4% for II. The interday precision for 0.55 and 2.11 micrograms/ml of each compound was 5.5 and 2.9% for I and 7.3 and 5.0% for II, respectively. This method has been applied in several pharmacokinetic studies.