Kuan Gandelman

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.

Steady-State Pharmacokinetic and Safety Profiles of Voriconazole and Ritonavir in Healthy Male Subjects

ABSTRACT 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 [AUC0-12], −82%; maximum concentration [Cmax], −66%). However, the effect of low-dose (100 mg BID) ritonavir was less pronounced (AUC0-12, −39%; Cmax, −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 (AUC0-12, −14%; Cmax, −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, 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-β-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).

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.

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) (AUCdn and Cmaxdn) were obtained by dividing each value by the administered dose. Dose-per-bodyweight normalized AUC and Cmax (AUCdn,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. AUCdn (Asian = 2.35, Caucasian = 2.06 [ng·hr·mL−1]/mg) and Cmaxdn (Asian = 0.39, Caucasian = 0.40 Cmaxdn,wt) and the equivalent dose-per-bodyweight normalized values for atorvastatin (AUCdn,wt: Asian = 157.5, Caucasian = 156.4 [ng·hr·mL−1]/[mg·kg−1]; Cmaxdn,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 Cmaxdn,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 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.

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.

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 α-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, α-hydroxy-alprazolam, and 4-hydroxy-alprazolam were similar in adolescent and adult subjects. The ratios of estimated geometric means for AUC(0-∞) 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-∞) 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.

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.

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

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.