Population pharmacokinetics of gabapentin in infants and children.

PURPOSE: To characterize gabapentin pharmacokinetics in infants and children using a population approach and to identify important demographic and/or physiologic determinants of gabapentin disposition. METHODS: Gabapentin was administered in single doses of 10 mg/kg (N=48 healthy subjects, age 1 month-12 years) or in multiple doses of 10-65 mg/kg per day (N=205 patients with epilepsy, age 2 months-13 years) at 08:00, 14:00, and 20:00. Serial concentration-time data from the healthy subjects were combined with sparse data obtained in patients and were modeled using NONMEM. RESULTS: Gabapentin oral clearance (l/h) was directly related to creatinine clearance (ml/min) with a slope of 0.116. The slope of the relationship was 36% greater in blacks than in subjects of other races. When oral clearance was normalized for body weight, young children (<5 years) had higher and more variable values than older children. Volume of distribution was related to body weight and appeared to differ between subjects and patients. Intersubject variability was approximately 30% for oral clearance and volume of distribution and was larger for the absorption rate constant and lag time. Residual variability, a measure of intrasubject variability and measurement error, was smaller in subjects than in patients. CONCLUSIONS: On a weight basis, 33% larger doses would be required in younger children (<5 years) to achieve the same exposure as older children.

Single-dose gabapentin pharmacokinetics and safety in healthy infants and children.

Gabapentin (Neurontin) is a gamma-aminobutyric acid analogue indicated in adults for adjunctive treatment of partial seizures with or without secondary generalization. Two studies were conducted to determine the single-dose pharmacokinetics of gabapentin in healthy subjects age 1 month to 12 years and to guide dose selection in safety and efficacy trials in pediatric patients. Forty-eight subjects were given single oral doses of gabapentin (10 mg/kg) while fasting. Enrollment was homogeneously distributed throughout the age range. Plasma samples were drawn predose and then serially for 24 hours postdose. Single doses of gabapentin were well tolerated by healthy pediatric subjects. Plots of pharmacokinetic parameters versus age suggested significant differences between younger (1 month to < 5 years) and older (> or =5 to 12 years) subjects. Mean area under the plasma concentration-time curve from zero to infinity (AUC(0-infinity)) was 25.6 microg x h/mL in younger subjects and 36.0 microg x h/mL in older subjects (p < 0.001). Corresponding mean peak plasma concentrations (Cmax) were 3.74 and 4.52 microg/ml (p < 0.05). Oral clearance (normalized for body weight) was 7.40 and 4.41 mL/min/kg in younger subjects and older subjects, respectively (p < 0.001). It was concluded that children between 1 month and < 5 years of age require approximately 30% higher daily doses of gabapentin than those > or =5 to 12 years of age.

Inter- and intra-subject variability in gabapentin absorption and absolute bioavailability.

UNLABELLED: Gabapentin (GBP) is a non-metabolized, non-plasma protein bound, renally excreted antiepileptic drug that is actively absorbed via the system L amino acid transporter. Previous studies have demonstrated that gabapentin displays dose-dependent absorption. OBJECTIVES: These studies were conducted to determine inter- and intra-subject variability of gabapentin absorption. Two prospective clinical studies in healthy adult volunteers were conducted. Coefficient of variation (CV) was used to express variability of gabapentin absorption. METHODS: Study A: 400-mg single dose, randomized, cross-over study to assess bioavailability of four different gabapentin formulations (n=20, 9 males, 11 females; mean age and weight 41 years, 75.1 kg). Plasma was serially collected up to 48 h and bioavailability (F) calculated post-dose to determine concentration-time curves (AUC). All four formulations were bioequivalent, thus repeated measures analysis was performed to assess inter-and intra-subject variability. Study B: 600-mg single dose study (n=50, 15 males, 35 females; mean age and weight 31.1 years, 72.7 kg) was conducted to determine inter-subject variability in gabapentin F. Urine was collected over 48 h and bioavailability (F) calculated. Urine and plasma gabapentin concentrations were measured by HPLC-UV. RESULTS: Study A: Overall mean (CV) of GBP AUC values was 34.1+/-24 ug/h per ml. Inter-subject CV for AUC was 22.5% and intra-subject CV was 12.1%. Study B: Overall mean (SD) GBP F was 49.3+/-13.6%. Inter-subject CV of F was 27.6%. DISCUSSION: The inter-subject variability in gabapentin absorption is substantially less than that of the inter-subject variability. This indicates that one would expect a wide range in gabapentin absorption between subjects; however, a much smaller variability within a subject. The within subject variability of gabapentin is small enough that plasma drug monitoring may be used to assess gabapentin absorption for a given subject and the benefit of dose individualization.

Transport of pregabalin in rat intestine and Caco-2 monolayers.

PURPOSE: The purpose of this study was to determine if the intestinal transport of pregabalin (isobutyl gamma-aminobutyric acid, isobutyl GABA), a new anticonvulsant drug, was mediated by amino acid carriers with affinity for large neutral amino acids (LNAA). METHODS: Pregabalin transport was studied in rat intestine and Caco-2 monolayers. An in vitro Ussing/diffusion chamber model and an in situ single-pass perfusion model were used to study rat intestinal transport. An in vitro diffusion chamber model was used to evaluate Caco-2 transport. RESULTS: In rat ileum, pregabalin transport was saturable and inhibited by substrates of intestinal LNAA carriers including neurontin (gabapentin), phenylalanine, and proline. Weak substrates of intestinal LNAA carriers (beta-alanine, gamma-aminobutyric acid, and methyl aminoisobutyric acid) did not significantly change pregabalin transport. In Caco-2 monolayers that showed a high capacity for phenylalanine transport, pregabalin transport was concentration- and direction-independent and equivalent in magnitude to the paracellular marker, mannitol. The in vitro and in situ rat ileal permeabilities of the LNAA carrier-mediated compounds neurontin, pregabalin, and phenylalanine correlated well with the corresponding in vivo human oral absorption. CONCLUSIONS: The transport of pregabalin was mediated by LNAA carriers in rat ileum but not in Caco-2 monolayers. Caco-2 was not an appropriate model for evaluating the in vivo human oral absorption of pregabalin and neurontin.

Effects of age and gender on single-dose pharmacokinetics of gabapentin.

PURPOSE: This study was conducted to evaluate the effect of age, age-related changes in renal function, and gender on the single-dose pharmacokinetics of orally administered gabapentin (GBP). METHODS: The pharmacokinetics of a single 400-mg oral dose of GBP were studied in 36 healthy subjects (18 men and 18 women) aged 20-78 years. Serial blood samples and total urine output were collected for 48 h after the dose. GBP concentrations in plasma and urine were measured by high-performance liquid chromatography, and pharmacokinetic parameters were calculated by noncompartmental methods. RESULTS: All subjects tolerated the drug well, with only mild symptoms reported. No change in maximal GBP plasma concentration (Cmax), time at which Cmax occurred (tmax), or apparent volume of distribution (V/F) with age was noted. A significant linear decline in apparent oral clearance (CL/F), elimination-rate constant (lambda z), and renal clearance (CLR) with increasing age was observed (p < 0.005). Because total urinary recovery of unchanged drug (an estimate of F for GBP) did not change with age, the decline in CL/F and lambda z can be explained by the decline in CLR. The only pharmacokinetic parameter that was significantly different between genders was Cmax, which was approximately 25% higher for women than for men (p = 0.016), consistent with gender differences in body size. CONCLUSIONS: The results of this study suggest that changes in renal function are responsible for age-related changes in GBP pharmacokinetics. Reduction of GBP dosage may be required in elderly patients with reduced renal function. The pharmacokinetics of GBP are similar in men and women.

Gabapentin bioavailability: effect of dose and frequency of administration in adult patients with epilepsy.

UNLABELLED: Gabapentin (GBP) is a non-metabolized antiepileptic drug that is eliminated by renal excretion and displays saturable, dose dependent absorption. The recommended dosing schedule for GBP is t.i.d. At large daily doses, oral bioavailability (F) may be improved by giving the daily dose more frequently. OBJECTIVE: To evaluate whether switching GBP dosage regimen from t.i.d. to q.i.d. results in increased oral bioavailability. METHODS: This study consisted of two parts; a computer simulated pharmacokinetic model and a clinical pharmacokinetic study in nine adult epileptic patients receiving 3600 mg/day and 11 receiving 4800 mg/day. All patients were evaluated during both t.i.d. and q.i.d. regimens. F were determined by calculation of percent of dose excreted unchanged using steady-state 24-h urine collections and were compared using a paired t-test. RESULTS: At 3600 mg/day, mean F following t.i.d. and q.i.d. dosing were 38.7+/-22.1% and 40.0+/-18.9%, respectively (P=0.738). At 4800 mg/day, mean F following t.i.d. and q.i.d. dosing were 29.2+/-16.2% and 35.6+/-17.6%, respectively (P=0.006). DISCUSSION: Good agreement was observed between values from this study and predicted values based on the pharmacokinetic model. Improved GBP F at doses of 3600 mg/day was not achieved with more frequent drug administration, and thus is not warranted. At 4800 mg/day, a 22% increase in F was observed with more frequent drug dosing. CONCLUSION: GBP F may be significantly increased by q.i.d. versus t.i.d. dosing, depending upon dose level. This increase in F however must be balanced against the inconvenience of more frequent dosing. Therapeutic drug level monitoring may aid in the evaluation of such pharmacokinetic maneuvers.

Contrasting nutrient effects on the plasma levels of an amino acid-like antiepileptic agent from jejunal administration in dogs.

The absorption of gabapentin was investigated by monitoring drug plasma levels as a function of time following midjejunal administration in mongrel dogs. From previous work, dose-dependent absorption had been postulated to be a consequence of carrier-mediated transport and a paracellular pathway had been postulated to contribute to the passive absorption component in mammalian small intestine. The potential for amino acid inhibition of the carrier-mediated absorption component was investigated by drug coinfusion with leucine and phenylalanine. The potential for monosaccharide-enhanced increases in drug absorption was studied by drug coinfusion with D-glucose and 3-O-methylglucose. While lower drug plasma levels were observed with amino acid coinfusion versus controls in each of the dogs studied, mean area under the plasma level time curves (AUC) were not statistically significantly different (p < or = 0.07). Monosaccharide coinfusion significantly increased gabapentin AUC over control studies (p < or = 0.014) and over coinfusion with L-system amino acids (p < or = 0.0025). Implications for the mechanisms of intestinal absorption of this amino acid-like antiepileptic drug in this canine model are discussed.

Disposition of gabapentin in anuric subjects on hemodialysis.

Gabapentin is an anticonvulsant drug, which in man is cleared solely by renal excretion and is not bound to plasma proteins. Because the clearance of gabapentin is dependent on renal function, the pharmacokinetics of gabapentin were investigated in anuric subjects maintained on hemodialysis. Plasma samples were obtained over an 8-day period after administration of single oral 400-mg doses of gabapentin. Pre- and post-dialyzer plasma samples and dialysate samples from quantitative collection of dialyzer effluent were obtained during hemodialysis sessions performed 2, 4, and 7 days after dosing. A mean (SD) maximum gabapentin plasma concentration of 6.0 (2.4) micrograms/mL was achieved at 4.7 (2.1) hours post-dose. The elimination half-life of gabapentin on non-hemodialysis days averaged 132 hours. Approximately 35% of the gabapentin dose was recovered in dialysate, and mean hemodialysis clearance of gabapentin was 142 (26) mL/min; approximately 93% of the dialyzer creatinine clearance. Gabapentin elimination half-life during hemodialysis was approximately 4 hours. Systemic plasma gabapentin concentrations increased approximately 30% during the first 2 hours after hemodialysis as a result of drug redistribution in the body. It is recommended that patients with end-stage renal disease maintained on hemodialysis receive an initial 300-mg to 400-mg gabapentin loading dose. Plasma gabapentin concentrations can be maintained by giving 200 to 300 mg of gabapentin after every 4 hours of hemodialysis.

Disposition of gabapentin (neurontin) in mice, rats, dogs, and monkeys.

Gabapentin, an analog of gamma-aminobutyric acid, exhibits anticonvulsant properties in both animal models and humans. Gabapentin pharmacokinetics was studied in laboratory animals using HPLC and radiometry. Oral bioavailability was 40% in monkeys administered 25 mg/kg, 79% in mice and rats receiving 50 mg/kg, and 80% in dogs administered 50 mg/kg. Binding to plasma proteins was < 3%. Maximum blood or plasma concentrations generally occurred within 2 hr of an oral dose. In rats and monkeys, increases in maximum plasma concentrations and/or areas under the curve were less than dose-proportional following oral administration, most likely because of saturable absorption. However, intravenous pharmacokinetics in rats were linear over the dosage range of 4-500 mg/kg. Mean intravenous elimination half-life was 1.7 hr in rats, 2.9 hr (14C only) in dogs, and 3.0 hr in monkeys. In rats and dogs, repeated administration did not alter gabapentin or 14C pharmacokinetics. Additionally, gabapentin did not induce hepatic cytochrome P450 monooxygenases in rats. There were no age- (rats only) or gender-associated changes in pharmacokinetic parameters. [14C]Gabapentin was extensively distributed to tissues. In the dog, gabapentin was metabolized to N-methylgabapentin (approximately 34% of dose); whereas metabolism in mouse, rat, and monkey was minimal (< 5%). The principal route of excretion was via urine. In summary, as an antiepileptic drug, gabapentin exhibited desirable pharmacokinetic properties, such as linear elimination kinetics, not highly bound to plasma proteins, not extensively metabolized, and not an inducer of hepatic cytochrome P450.

Lack of interaction of gabapentin with carbamazepine or valproate.

Gabapentin (GBP) studies were conducted in patients with epilepsy receiving carbamazepine (CBZ, n = 12) or valproate (VPA, n = 14) monotherapy. The effects of GBP coadministration on steady-state CBZ or VPA concentrations and of these antiepileptic drugs (AEDs) on GBP pharmacokinetics were investigated. GBP (400 mg) was coadministered every 8 h for 3 1/3 days with CBZ or for 5 1/3 days with VPA. GBP was well tolerated. Mean steady-state plasma CBZ/CBZ-10,11-epoxide (CBZ-E) and serum VPA concentrations before, during, and after GBP administration were not significantly different. Mean steady-state GBP pharmacokinetic parameters during CBZ or VPA coadministration were similar to steady-state parameters reported in healthy subjects. Thus, no pharmacokinetic interaction exists between CBZ or VPA and GBP. No dosage adjustment is necessary when GBP and CBZ or VPA are coadministered.

Pharmacokinetics, mass balance, and induction potential of a novel GABA uptake inhibitor, CI-966 HCl, in laboratory animals.

CI-966 exhibits anticonvulsant properties in various animal models. The drug acts by inhibiting synaptic uptake of gamma-aminobutyric acid (GABA). Oral absorption of CI-966 in dogs given 1.39 mg/kg is rapid with a tmax of 0.7 hr. In rats given 5 mg/kg oral, a mean tmax of 4.0 hr was observed. Following iv administration of the same respective doses, elimination t1/2 in dogs and rats averaged 1.2 and 4.5 hr. Absolute oral bioavailability of CI-966 was 100% in both species. Following oral dosing of [14C]CI-966 HCl to dogs, fecal, and urinary excretion accounted for 89% and 2.3% of the 14C dose, respectively. In bile-duct cannulated rats, biliary excretion is the major elimination pathway of radioactivity (75%). Urinary and fecal excretion accounted for 4.1 and 12%, respectively. CI-966 does not induce or inhibit mouse hepatic mixed function oxidases, as determined by hexobarbital sleeping time.

Measurement of CI-979 (a candidate drug for the treatment of age-related disorders of cognition) in human plasma by capillary gas chromatography with nitrogen-selective detection.

A specific and highly sensitive method for the measurement of CI-979 in human plasma is described. The compound and internal standard were extracted from alkalinized plasma with methyl tert.-butyl ether and analyzed by capillary gas chromatography with nitrogen-selective detection. The method was demonstrated to be accurate and precise. Since the limit of quantitation was 0.10 ng/ml, this method was suitable for clinical pharmacokinetic studies in which subjects received repeated administration of 0.5-2.5 mg CI-979 every 6 h.

A saturable transport mechanism in the intestinal absorption of gabapentin is the underlying cause of the lack of proportionality between increasing dose and drug levels in plasma.

Gabapentin (1-(aminomethyl)cyclohexaneacetic acid) is a neuroprotective agent with antiepileptic properties. The structure is small (molecular weight less than 200), is zwitterionic, and resembles an amino acid with the exception that it does not contain a chiral carbon and the amino group is not alpha to the carboxylate functionality. Gabapentin is not metabolized by humans, and thus, the amount of gabapentin excreted by the renal route represents the fraction of dose absorbed. Clinical trials have reported dose-dependent bioavailabilities ranging from 73.8 +/- 18.3 to 35.7 +/- 18.3% when the dose was increased from 100 to 1600 mg. The permeability of gabapentin in the rat intestinal perfusion system was consistent with carrier-mediated absorption, i.e., a 75 to 80% decrease in permeability when the drug concentration was increased from 0.01 to 50 mM (0.46 +/- 0.05 to 0.12 +/- 0.04). Excellent agreement was obtained between the actual clinical values and the predicted values from in situ results for the fraction of dose absorbed calculated using the theoretically derived correlation, Fabs = 1 - exp(-2Peff) by Amidon et al. (Pharm. Res. 5:651-654, 1988). The permeability values obtained for gabapentin correspond to 67.4 and 30.2% of the dose absorbed at the low and high concentrations, respectively. In the everted rat intestinal ring system, gabapentin shared an inhibition profile similar to that of L-phenylalanine. Characteristics of gabapentin uptake included cross-inhibition with L-Phe, sensitivity to inhibition by L-Leu, stereoselectivity as evidenced by incomplete inhibition by D-Phe, and lack of effect by Gly.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of cimetidine administration on the pharmacokinetics of pirmenol.

The potential for a drug-drug interaction between pirmenol, an extensively metabolized antiarrhythmic agent, and cimetidine, an inhibitor of hepatic drug-metabolizing enzymes, was evaluated in eight healthy adults. A single 150-mg oral dose of pirmenol was administered on study days 1 and 8 and oral cimetidine, 300-mg QID, was administered on study days 4 through 11. Plasma and urine samples were collected after each pirmenol dose for determination of pirmenol concentration. Mean pirmenol concentration-time curves and pharmacokinetic parameters, including elimination rate constant, were not significantly altered by concomitant administration of cimetidine.

Stereoselective high-performance liquid chromatographic assay for pirmenol enantiomers in dog plasma.

Pirmenol enantiomers in dog plasma were quantified using a stereospecific high-performance liquid chromatographic method with ultraviolet detection at 262 nm. Racemic pirmenol and internal standard, (+)-propranolol, were isolated from dog plasma by a three-step extraction procedure using toluene, 0.1 M hydrochloric acid and hexane, respectively. A chiral analytical column (Chiralcel OJ) was used with a mobile phase consisting of hexane-isopropanol-diethylamine (98.9:1.0:0.1). Linear calibration curves were obtained in the concentration range 0.0200-5.00 micrograms/ml for each enantiomer. Precision of the method, expressed as coefficient of variation for nine quality control samples, was 7.1% for (+)-pirmenol and 6.4% for (-)-pirmenol. Bias was +/- 2.2% for (+)-pirmenol and +/- 1.5% for (-)-pirmenol in quality control samples.

Formation of [20R]-dihydrodigoxin from digoxin in humans.

The objective of this research was to determine the stereochemical identity of dihydrodigoxin (DHD3), a metabolite of digoxin excreted in urine after digoxin administration in man. Separation of the individual epimers in reference DHD3 was effected by a chemical derivatization-HPLC procedure. Comparison of individual derivatized epimers of DHD3 with the known 20R and 20S epimers of derivatized dihydrodigoxigenin using chromatographic data and NMR spectroscopy permitted identification of the 20R and 20S epimers in reference DHD3. Material corresponding chromatographically to R-DHD3 was isolated from urine of a volunteer taking oral digoxin daily. The NMR spectrum of the chromatographically pure, derivatized urinary isolate was identical to the NMR spectrum of derivatized R-DHD3. Urine samples from 20 patients on chronic digoxin therapy and from two volunteers were surveyed for chromatographic evidence of R- or S-DHD3 using HPLC of a fluorescent derivative as well as HPLC of a UV-absorbing derivative. The more sensitive fluorescence procedure yielded evidence for R-DHD3 in eight patients and both volunteers. There was a sufficient concentration in four patients and both volunteers for independent evidence of R-DHD3 using the UV-absorbing derivative. Chromatographic evidence (fluorescent derivative) for S-DHD3 was found in urine from three patients. However, this evidence for S-DHD3 was demonstrated to be an artifact by the absence of the peak expected for S-DHD3 in the chromatogram of the UV-absorbing derivative as well as by the inability of fecal incubates to convert digoxin to S-DHD3. The results of the investigation indicate that the DHD3 metabolite formed in humans is the 20R epimer.

Digoxin and metabolites in urine: a derivatization--high-performance liquid chromatographic method capable of quantitating individual epimers of dihydrodigoxin.

A high-performance liquid chromatographic method is described for the determination of digoxigenin, digoxigenin monodigitoxoside, digoxigenin bis-digitoxoside, digoxin, and dihydrodigoxin as the 3,5-dinitrobenzoyl esters. The method is applied to a 10 ml urine sample by adding digitoxigenin as internal standard, extracting with methylene chloride, derivatizing with 3,5-dinitrobenzoyl chloride in pyridine, chromatographing with a normal-phase system and detecting at 254 nm. Derivatized digoxigenin, digoxigenin mono- and bis-digitoxoside, and digoxin each yielded one symmetrical peak with the limit of sensitivity of the method being approximately 100 ng/ml. Analysis of a commercially obtained sample of dihydrodigoxin resulted in two well-separated, symmetrical peaks that represent the two epimers of derivatized dihydrodigoxin. Data indicate rapid and complete esterification of all primary and secondary alcohol moieties in the various molecules and the derivatives are shown to be stable in chloroform for at least four days. The procedure appears to be suitable for metabolic investigations and as a prototype for future analytical developments.

Comparison of bioavailability and pharmacokinetics of cimetidine in subjects with normal and impaired renal function.

The bioavailability and pharmacokinetics of cimetidine were studied following single oral and intravenous doses in subjects with severely impaired renal function (SIRF) and normal renal function (NRF). Eight subjects with NRF and five patients with SIRF participated. Multiple blood samples were obtained up to 1440 minutes following both doses. Urine was also collected for 24 hours after each dose. The bioavailability of cimetidine was not significantly different between the two groups (78 +/- 15% in patients with SIRF and 62 +/- 17% in the NRF subjects). In subjects with NRF, a mean of 50.4% of the i.v. dose was excreted renally as unchanged drug and the mean serum half-life (t1/2) was 2.00 hours. The mean total body and renal clearances were 710.0 and 370.7 ml/min, respectively. In the SIRF group, a mean of 1.7% of the i.v. dose was excreted renally unchanged, and the mean t1/2 was 12.71 hours. The total body and renal clearances were 147.1 and 2.5 ml/min, respectively. Nonrenal clearance was 62% lower in the subjects with SIRF than in the NRF subjects. There is no significant difference in bioavailability of cimetidine between the patients with NRF and SIRF. The significantly lower nonrenal clearance of the patients with SIRF suggests that cimetidine metabolism may be impaired in uremic patients.

Spectral analysis of the configuration and solution conformation of dihydrodigoxigenin epimers.

The C20 configuration and solution conformation of each epimer of dihydrodigoxigenin has been studied by circular dichroism (CD) and NMR spectroscopy. Results from the CD spectra indicate that the two epimers have opposite orientations of the beta-carbon in the lactone ring. This finding, together with X-ray crystallographic data from a separate study on the minor epimer, establishes the C20 configuration of the minor epimer as S and of the major epimer as R. NMR evidence indicates that the average lactone rotamer for the minor epimer has the C22 position located on the C12 side of the steroid nucleus, whereas the average lactone rotamer for the major epimer has the C21 position located on the C12 side of the steroid nucleus. Molecular models indicate that these are the least-hindered positions for the respective rotamers. Physical data characterizing the two epimers are provided.