The impact of gastric pH, volume, and emptying on the food effect of ziprasidone oral absorption.

In a recent food effect clinical study, the authors concluded that a meal consisting of ≥500 kcal, regardless of fat content, produced the maximal bioavailability for ziprasidone. Using GastroPlus™, a commercially available pharmacokinetic simulation software, a semiphysiological model-a kind of physiologically based pharmacokinetic (PBPK) absorption model-was developed that could predict the concentration-time profiles when ziprasidone was administered with any one of the five test meals or fasting. Ziprasidone intravenous pharmacokinetics and oral absorption permeability were determined from clinical studies following the intravenous and duodenal infusion of ziprasidone to volunteers. From the detailed dietary information of each meal provided in the previously published food effect study, the stomach pH, volume, and gastric emptying could be predicted. Incorporating these meal-specific parameters into the model improved the predictions beyond the default fed/fasted parameters commonly used in the software. Compared to the default models, the improved models resulted in an improved prediction of the average ziprasidone concentration-time profile for each meal. Using this type of semiphysiological absorption model, we have shown that the dietary contents of the meals should be taken into account to predict food effects for ziprasidone and perhaps other BCS class I or II compounds.

Population pharmacokinetics of pegaptanib sodium (Macugen(®)) in patients with diabetic macular edema.

OBJECTIVE: Population pharmacokinetic modeling of pegaptanib was undertaken to determine influence of renal function on apparent clearance. METHODS: In a randomized, double-masked multicenter trial, intravitreal pegaptanib (0.3, 1.0, or 3.0 mg/eye) was administered in patients with diabetic macular edema every 6 weeks for 12-30 weeks. A one-compartment model with first-order absorption, distribution volume, and clearance was used to characterize the pegaptanib plasma concentration-time profile. RESULTS: In 58 patients, increases in area under the concentration-time curve (AUC) to end of the dosing interval (AUC0-tau) and maximum concentration with repeat doses were <6%, indicating minimal plasma accumulation. Sex and race did not have clinically significant effects on pegaptanib exposure. In the final model, the AUC extrapolated to infinite time and maximum concentration increased by ≥50% in older patients (aged >68 years) relative to younger patients due to decreases in creatinine clearance (CRCL), a significant predictor of clearance. Pegaptanib clearance was reduced by 29% when CRCL decreased by 50%. The change in exposure with CRCL (range, 0-190 mL/minute) was < 10-fold with 0.3-3.0 mg doses. CONCLUSION: While pegaptanib clearance and AUC were significantly influenced by CRCL, the predicted exposure in patients with renal insufficiency or renal failure shows no evidence that a dose adjustment is warranted, given the tenfold margin of safety observed over the dose range of 0.3-3.0 mg.

Effect of food on the pharmacokinetics of oxycodone and naltrexone from ALO-02, an extended release formulation of oxycodone with sequestered naltrexone.

WHAT IS KNOWN AND OBJECTIVE: ALO-02 is being developed as an abuse-deterrent formulation of extended-release oxycodone hydrochloride with naltrexone hydrochloride sequestered in the core of pellets contained in capsules. The primary objective of this study was to assess the effects of administration of ALO-02 capsule whole under fed conditions or sprinkling the pellets from ALO-02 capsule on applesauce under fasting conditions on the pharmacokinetics (PK) of oxycodone, naltrexone and 6-ß-naltrexol compared with ALO-02 capsule administered whole under fasting conditions. The plasma naltrexone and 6-ß-naltrexol concentrations were used to assess the sequestration of naltrexone in the ALO-02 formulation. The secondary objective was to evaluate the safety and tolerability of single 40 mg doses of ALO-02 in healthy volunteers. METHODS: This was an IRB-approved, open-label, single-dose, randomized, 3-period crossover study in 24 healthy adult volunteers, aged 18-55 years. Each subject was assigned to receive single 40 mg doses of ALO-02 administered whole (intact capsule) under fasting conditions, administered whole under fed conditions (high-fat breakfast ∼ 950 calories), or sprinkling the contents of the ALO-02 capsule (pellets) over applesauce and swallowing the dose without chewing under fasting conditions. Each treatment was separated by a 7-day washout interval. Plasma samples were analyzed just before dosing through 48 hours postdose for oxycodone, and through 120 hours postdose for naltrexone and its major metabolite, 6-ß-naltrexol. Pharmacokinetic parameters included maximum plasma concentration [Cmax ], area under the plasma concentration-time profile from time 0 to infinity [AUCinf ] and to the last quantifiable concentration [AUClast ], time to Cmax [Tmax ], and terminal half life [t1/2 ]. Adverse events, vital signs, and laboratory parameters were monitored for safety assessment. RESULTS: The t1/2 and Tmax values for oxycodone were similar for all 3 treatments. There was a lack of effect of food (whole capsule, fed vs. fasted) or of sprinkling on applesauce (pellets vs. whole capsule, fasted) on oxycodone bioavailability. The Test/Reference ratios of adjusted geometric means for oxycodone AUCinf , AUClast , and Cmax were 99.2%, 100%, and 107%, respectively, for the effect of food; and 101%, 101%, and 97.5%, respectively, for the effect of sprinkling on applesauce. The 90% confidence intervals contained entirely within the bioequivalence limits of 80% to 125% for each comparison. Naltrexone remained sequestered during each treatment, based on the sporadic and low measurable plasma concentrations of naltrexone and 6-ß-naltrexol. Single doses of ALO-02 40 mg were well tolerated, and adverse events were mild, with no apparent difference in frequency for all 3 treatments. WHAT IS NEW AND CONCLUSION: Results indicate that ALO-02 can be administered without regard to food. Also, the contents of ALO-02 can be sprinkled over applesauce and consumed without chewing as an alternative treatment option by subjects with difficulty swallowing. Naltrexone remained sequestered in the ALO-02 formulation under all 3 treatments.

Population pharmacokinetics of atorvastatin and its active metabolites in children and adolescents with heterozygous familial hypercholesterolemia: selective use of informative prior distributions from adults.

The population pharmacokinetics (PPK) of atorvastatin and its principal active metabolite, o-hydroxyatorvastatin, were described in 6-17 years old pediatric hypercholesterolemia patients with a 2-compartment model for both parent and metabolite. Informative prior distributions on selected parameters, based on adult data, were required to stabilize the model and were implemented using a Bayesian penalty term on the likelihood function in the nonlinear mixed effects model (NONMEM VI with PRIOR). Concentrations below the limit of quantitation were treated as censored data using a conditional likelihood function. Atorvastatin apparent oral clearance (CL/F) was described as a function of body weight using an allometric equation. Based on the final model, the typical CL/F estimates for a Tanner Stage 1 patient (35 kg weight) and Tanner Stage ≥2 (50 kg weight), would be 553 and 543 L/hour, respectively. When scaled allometrically, CL/F was similar to values reported for adults. Variability in atorvastatin PK was primarily affected by weight.

Systemic exposure to atorvastatin between Asian and Caucasian subjects: a combined analysis of 22 studies.

The aim of the present study was to determine whether there is a differing pattern of systemic exposure to atorvastatin in Asian versus Caucasian subjects by comparison of data obtained from completed pharmacokinetic studies. Pharmacokinetic data were analyzed from completed single-dose (10-80 mg) studies in Asian and Caucasian subjects. Dose normalized area under the concentration-time curve (AUC) and maximum observed concentration (Cmax) (AUC(dn) and Cmax(dn)) were obtained by dividing each value by the administered dose. Dose-per-bodyweight normalized AUC and Cmax (AUC(dn,wt) and Cmax,(dn,wt)) were obtained by dividing each value by the administered dose per unit bodyweight. Mean difference and 90% confidence intervals for Asian versus Caucasian comparisons were calculated for atorvastatin pharmacokinetic values based on the t statistic and expressed as ratios using Caucasians as the reference. Data were analyzed from 310 Asians and 579 Caucasians from 22 studies. AUC(dn) (Asian = 2.35, Caucasian = 2.06 [ng·hr·mL(-1)]/mg) and Cmax(dn) (Asian = 0.39, Caucasian = 0.40 Cmax(dn,wt)) and the equivalent dose-per-bodyweight normalized values for atorvastatin (AUC(dn,wt): Asian = 157.5, Caucasian = 156.4 [ng·hr·mL(-1)]/[mg·kg(-1)]; Cmax(dn,wt): Asian = 26.2, Caucasian = 30.3 [ng·mL(-1)]/[mg·kg(-1)]) were similar in both ethnic groups. Mean differences and 90% confidence interval for the differences fell within the limits (0.8-1.25) except for Cmax(dn,wt), for which the lower limit was slightly below 80%. No differences were noted in the systemic exposure to atorvastatin between Asian and Caucasian subjects. These data therefore demonstrate that dosing considerations in the current labels for atorvastatin are similar for Asian compared with Caucasian subjects.

Effects of the moderate CYP3A4 inhibitor, fluconazole, on the pharmacokinetics of fesoterodine in healthy subjects.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Available data suggest that fesoterodine dosage should not exceed 4 mg once daily when taken concomitantly with potent CYP3A4 inhibitors, such as ketoconazole. Currently, no information is available on whether dose adjustment is necessary when fesoterodine is administered with a moderate CYP3A4 inhibitor. WHAT THIS STUDY ADDS: This study shows that adjustment of fesoterodine dose is not warranted when co-administered with a moderate CYP3A4 inhibitor. AIMS: To assess the effects of fluconazole, a moderate CYP3A4 inhibitor, on the pharmacokinetics (PK) and safety/tolerability of fesoterodine. METHODS: In this open-label, randomized, two-way crossover study, 28 healthy subjects (18-55 years) received single doses of fesoterodine 8 mg alone or with fluconazole 200 mg. PK endpoints, including the area under the plasma concentration-time curve from 0 to infinity (AUC(0,∞)), maximum plasma concentration (C(max) ), time to C(max) (t(max) ), and half-life (t(1/2) ), were assessed for 5-hydroxymethyl tolterodine (5-HMT), the active moiety of fesoterodine. RESULTS: Concomitant administration of fesoterodine with fluconazole increased AUC(0,∞) and C(max) of 5-HMT by approximately 27% and 19%, respectively, with corresponding 90% confidence intervals of (18%, 36%) and (11%, 28%). There was no apparent effect of fluconazole on 5-HMT t(max) or t(½) . Fesoterodine was generally well tolerated regardless of fluconazole co-administration, with no reports of death, serious adverse events (AEs) or severe AEs. Following co-administration of fesoterodine with fluconazole, 13 subjects (48%) experienced a total of 40 AEs; following administration of fesoterodine alone, six subjects (22%) experienced a total of 19 AEs. The majority of AEs were of mild intensity. There were no clinically significant changes in laboratory or physical examination parameters. CONCLUSION: Fesoterodine 8 mg single dose was well tolerated when administered alone or with fluconazole. Based on the observed increase in 5-HMT exposures being within the inherent variability of 5-HMT pharmacokinetics, adjustment of fesoterodine dose is not warranted when co-administered with a moderate CYP3A4 inhibitor provided they are not also inhibitors of transporters.

Effects of fesoterodine on the pharmacokinetics and pharmacodynamics of warfarin in healthy volunteers.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Drug-drug interactions with warfarin are common with potentially harmful consequences. Preclinical in vitro studies suggest that fesoterodine or 5-hydroxymethyl tolterodine are not likely to affect warfarin metabolism, but a lack of interaction has not been demonstrated in a clinical study. WHAT THIS STUDY ADDS: This study shows that the pharmacokinetics and pharmacodynamics of warfarin 25 mg in healthy adults are unaffected by fesoterodine 8 mg, and that co-administration of warfarin 25 mg and fesoterodine 8 mg is safe and well tolerated. AIMS: To confirm the lack of an interaction of fesoterodine 8 mg with warfarin pharmacokinetics and pharmacodynamics in healthy adults. METHODS: In this open-label, two-treatment, crossover study, subjects (n= 14) aged 20-41 years with normal prothrombin time (PT) and International Normalized Ratio (INR) were randomized to receive a single dose of warfarin 25 mg alone in one period and fesoterodine 8 mg once daily on days 1-9 with a single dose of warfarin 25 mg co-administered on day 3 in the other period. There was a 10-day washout between treatments. Pharmacokinetic endpoints were area under the plasma concentration-time curve from time 0 to infinity (AUC(0,∞)), maximum plasma concentration (C(max)), AUC from time 0 to the time of the last quantifiable concentration (AUC(0,last)), time to C(max) (t(max) ), and half-life (t(1/2)) for S- and R-warfarin. Pharmacodynamic endpoints were area under the INR-time curve (AUC(INR) ), maximum INR (INR(max)), area under the PT-time curve (AUC(PT)) and maximum PT (PT(max)). RESULTS: Across all pharmacokinetic and pharmacodynamic comparisons, the point estimates of treatment ratio (warfarin co-administered with fesoterodine vs. warfarin alone) were 92-100%. The 90% confidence intervals for the ratios of the adjusted geometric means were contained within (80%, 125%). There were no clinically relevant changes in laboratory tests, vital signs or ECG recordings. CONCLUSIONS: The pharmacokinetics and pharmacodynamics of warfarin 25 mg in healthy adults are unaffected by fesoterodine 8 mg. Concomitant administration of fesoterodine and warfarin was well tolerated.

An eight-week trial investigating the efficacy and tolerability of atorvastatin for children and adolescents with heterozygous familial hypercholesterolemia.

This study aimed to assess the efficacy and tolerability of atorvastatin in Tanner stage (TS) 1 patients ages 6 to 10 years and TS ≥ 2 patients ages 10 to <18 years with genetically confirmed heterozygous familial hypercholesterolemia (HeFH) and a low density lipoprotein cholesterol (LDL-C) level of 4 mmol/l (155 mg/dl) or higher. In this open-label, 8-week study, 15 TS 1 children were treated initially with atorvastatin 5 mg/day and 24 TS ≥ 2 children with 10 mg/day. Doses were doubled at week 4 if the LDL-C target (<3.35 mmol/l [130 mg/dl]) was not achieved. The efficacy variables were the percentage change from baseline in LDL-C, total cholesterol (TC), triglycerides (TG), high density lipoprotein cholesterol (HDL-C), very low density lipoprotein cholesterol (VLDL-C), and apolipoprotein (Apo) A-I and Apo B. Safety evaluations included clinical monitoring, subject-reported adverse events (AEs), vital signs, and clinical laboratory tests. The mean values for LDL-C, TC, VLDL-C, and Apo B decreased by week 2 among all TS 1 and TS ≥ 2 patients, whereas TG, HDL-C, and Apo A-I varied considerably from week to week. After 8 weeks, the mean reduction in LDL-C was -40.7% ± 8.4 for the TS 1 children and -39.7% ± 10.3 for the TS ≥ 2 children. For the TS 1 patients, the mean reductions were -34.1% ± 6.9 for TC and -6.0% ± 32.1 for TG. The corresponding changes for the TS ≥ 2 patients were -35.6% ± 9.5 for TC and -21.1% ± 29.7 for TG. Four patients experienced mild to moderate treatment-related AEs. No serious AEs or discontinuations were reported. Overall, no difference in safety or tolerability was observed between the younger and older cohorts. Across the range of exposures after atorvastatin 5 to 10 mg (TS 1) or atorvastatin 10 to 20 mg (TS ≥ 2) doses for 8 weeks, clinically meaningful reductions in LDL-C, TC, VLDL-C, and Apo were observed with atorvastatin in pediatric patients who had HeFH. Atorvastatin also was well tolerated in this population.

Unexpected effect of rifampin on the pharmacokinetics of linezolid: in silico and in vitro approaches to explain its mechanism.

The effect of rifampin on the steady-state pharmacokinetics of linezolid was evaluated in an open-label, multiple-dose, crossover study in 16 healthy subjects. When coadministered with rifampin, area under the plasma concentration-time curve over the dosing interval and maximum concentration values for linezolid were reduced approximately 32% and 21%, respectively. Time to maximum concentration and apparent volume of distribution were generally similar between treatments. The mean half-life and apparent oral clearance were decreased for the combination treatment compared with linezolid alone. In vitro and in silico approaches were used to evaluate this interaction. In human hepatocytes, the metabolism of linezolid was increased by 1.3- to 1.6-fold when the cells were pretreated with rifampin, compared with a 19- to 40-fold increase in testosterone metabolism, a positive control for cytochrome P4503A activity. This increase in linezolid and testosterone metabolism was partially inhibited (~50%) by ketoconazole. Modeling of these data using Simcyp suggested that rifampin inducible drug metabolizing enzymes, such as cytochrome P4503A, have a very minor contribution to linezolid clearance, which increases when rifampin is coadministered. The clinical significance of the decreased linezolid levels is unclear. Linezolid and rifampin administered alone or in combination was generally safe and well tolerated.

Assessment of the effects of renal impairment on the pharmacokinetic profile of fesoterodine.

The effects of renal impairment on the pharmacokinetics of a single 4-mg oral dose of fesoterodine are assessed in 8 healthy subjects and 8 subjects each with mild, moderate, or severe renal impairment. Compared with findings in healthy subjects, the maximum concentration in plasma of 5-hydroxymethyl tolterodine (5-HMT), the principal active moiety of fesoterodine, increases by 1.4-, 1.5-, and 2.0-fold and area under the curve increases by 1.6-, 1.8-, and 2.3-fold in subjects with mild, moderate, and severe renal impairment, respectively. There is a clear correlation between the renal clearance of 5-HMT and creatinine clearance. The median time of observed maximum drug concentration (5-6 hours) and mean terminal half-life (6-7 hours) of 5-HMT are unaffected by renal impairment. The unbound fraction of 5-HMT in plasma (0.43-0.54 ng/mL) is comparable across all groups. In conclusion, because of the involvement of both metabolic and renal elimination pathways, only modest increases in 5-HMT exposures are observed in patients with renal impairment.

The impact of calories and fat content of meals on oral ziprasidone absorption: a randomized, open-label, crossover trial.

BACKGROUND: Food is known to increase the bioavailability of ziprasidone. Therefore, we evaluated the effects of meals of differing caloric and fat content on steady-state ziprasidone exposure in a stable, treated group of subjects with DSM-IV diagnoses of schizophrenia, schizoaffective disorder, bipolar disorder, or psychotic disorder (not otherwise specified) who were already receiving oral ziprasidone as their standard therapy. METHOD: Patients took ziprasidone under 6 meal conditions in randomized sequences (fasted, low calorie/low fat, low calorie/high fat, medium calorie/high fat, high calorie/low fat, and high calorie/high fat); each crossover period was separated by at least 3 days for washout of the previous meal condition. Serial blood samples were obtained over the 12 hours postdose. The study was conducted from July 27 to September 28 of 2006. RESULTS: Maximum ziprasidone exposures in this study were observed with high-calorie meals (1000 kcal), which were nearly twice those observed under fasting conditions. The medium-calorie meal (500 kcal) was associated with exposures similar to the high-calorie meals. Low-calorie meals (250 kcal) were associated with exposures that were approximately 60% to 90% lower than those of medium- and high-calorie meals, and approached exposures seen under fasting conditions. Fat content of the meal had no significant effect on ziprasidone absorption. The ziprasidone exposures observed with medium- and high-calorie meals had less variability than those with low-calorie meals and under fasting conditions. CONCLUSIONS: These results confirm that ziprasidone should be taken with food and that a meal equal to or greater than 500 kcal, irrespective of fat content, is required for optimal and reproducible bioavailability of the administered dose.

Pharmacokinetics, safety and tolerance of voriconazole in renally impaired subjects: two prospective, multicentre, open-label, parallel-group volunteer studies.

BACKGROUND AND OBJECTIVES: Since little is known regarding the pharmacokinetics of voriconazole in renally impaired patients, two prospective, open-label, parallel-group volunteer studies were conducted to estimate the effect of renal impairment on the pharmacokinetics of oral voriconazole and intravenous voriconazole solubilized with sulphobutylether-beta-cyclodextrin (SBECD), respectively. METHODS: In study A, male subjects with no (n = 6), mild (n = 6), moderate (n = 6) or severe (n = 6) renal impairment received one 200 mg dose of oral voriconazole. Voriconazole plasma levels were periodically assessed until 48 hours post-dose. In study B, male subjects with no (n = 6) or moderate (n = 7) renal impairment received multiple doses of intravenous voriconazole solubilized with SBECD (6 mg/kg twice daily [day 1] then 3 mg/kg twice daily [days 2-6] followed by a final dose of 3 mg/kg on the morning of day 7) at an infusion rate of 3 mg/kg/h. Voriconazole plasma levels were periodically assessed until 36 hours following the final dose. Pharmacokinetics were determined by non-compartmental methods. RESULTS: The pharmacokinetics of voriconazole were unaffected in subjects with any degree of renal impairment in both studies. In study B, clearance of SBECD was proportional to creatinine clearance (r2 = 0.857). Although two subjects had >30% increase in serum creatinine from baseline, these changes did not correlate with SBECD trough levels (r2 = 0.053). The majority of subjects with moderate renal insufficiency were able to tolerate 7 days of intravenous voriconazole solubilized with SBECD. CONCLUSION: These data suggest that renal impairment does not affect the pharmacokinetics of voriconazole. Furthermore, in subjects with moderate renal impairment, there is a strong linear correlation between SBECD clearance and creatinine clearance, and elevated SBECD levels do not necessarily correlate with increased serum creatinine levels (an indicator of worsening renal function).

Steady-state pharmacokinetic and safety profiles of voriconazole and ritonavir in healthy male subjects.

Since there is a likelihood of coadministration of voriconazole and ritonavir, two studies were conducted to evaluate the potential of drug interaction. Study A was a randomized, placebo-controlled, two-period, parallel-group trial (n = 34). Study B had the same design without the placebo group (n = 17). In period 1, subjects received 200 mg voriconazole or placebo twice daily (BID) for 3 days (400 mg BID on day 1). In period 2, following a 7-day washout, subjects received ritonavir alone at 400 mg BID (study A) or 100 mg BID (study B) for 10 days (days 11 to 20), and then ritonavir was coadministered with 200 mg BID voriconazole or placebo for the next 10 days (days 21 to 30). Serial plasma samples were collected on days 3, 20, and 30, and safety data were collected throughout the study. High-dose (400 mg BID) ritonavir substantially reduced the steady-state mean voriconazole exposure (area under the concentration-time curve from 0 to 12 h [AUC(0-12)], -82%; maximum concentration [C(max)], -66%). However, the effect of low-dose (100 mg BID) ritonavir was less pronounced (AUC(0-12), -39%; C(max), -24%). The decrease in voriconazole exposure was probably due to the induction of CYP2C19 and CYP2C9 by ritonavir. It is interesting that one subject in each study exhibited the opposite effect of ritonavir on voriconazole exposure (a 2.5- to 3-fold increase), probably due to lack of CYP2C19. Voriconazole had no apparent effect on the exposure of high-dose ritonavir but slightly decreased the exposure of low-dose ritonavir (AUC(0-12), -14%; C(max), -24%). The safety profile of combination therapy was not notably different from that of voriconazole or ritonavir alone. Due to the significant effect of ritonavir on voriconazole exposure, coadministration of voriconazole with 400 mg BID ritonavir is contraindicated; coadministration with 100 mg BID ritonavir should be avoided, unless an assessment of the benefit/risk to the patient justifies the use.

Pharmacokinetics of an extended release formulation of alprazolam (Xanax XR) in healthy normal adolescent and adult volunteers.

The purpose of this study was to estimate pharmacokinetics, safety, and tolerability of single doses of an extended release formulation of alprazolam (Xanax XR) in adolescent and adult healthy volunteers. This was a randomized, open-label, single-dose, 2-period crossover study. Twelve adolescent healthy volunteers (13-17 years) and 12 adult healthy volunteers (20-45 years) received single doses of Xanax XR 1 mg or 3 mg tablets. Blood samples were obtained predose and for 48 hours postdose. Plasma samples were assayed for alprazolam and its two active metabolites alpha-hydroxy-alprazolam and 4-hydroxy-alprazolam using a validated LC-MS/MS method. Safety assessments included clinical laboratory tests, vital signs, and adverse event monitoring. At both dose levels, mean plasma concentration-time profiles of alprazolam, alpha-hydroxy-alprazolam, and 4-hydroxy-alprazolam were similar in adolescent and adult subjects. The ratios of estimated geometric means for AUC(0-infinity) and Cmax between adolescents and adults for both dose levels were 115% (95% CI: [93, 143]) and 111% (95% CI: [95, 129]), respectively. An assessment of dose proportionality between the 3 mg and 1 mg alprazolam doses within both age groups indicated that the AUC(0-infinity) and Cmax were both within 80-125% equivalence limits. Parent-metabolite ratios were similar in both age groups and were consistent with those previously reported. Alprazolam was well tolerated by both age groups. The most common adverse event was somnolence, which occurred in a dose-related manner. Based on the similar pharmacokinetic profiles, dosing of Xanax XR should be similar in adolescents and adults.