G R Granneman

Abbott Laboratories, North Chicago, IL, United States

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Publications (96)440.4 Total impact

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    ABSTRACT: Extended-release divalproex sodium (divalproex-ER) biopharmaceutics after every-12-hour (q12h) administration was compared with that of once-daily divalproex-ER and conventional divalproex given every 6 hours (q6h) in a multiple-dose (14-day), randomized, three-period crossover design study in 24 patients with epilepsy concomitantly receiving enzyme-inducing antiepileptic medication(s). Plasma valproic acid (VPA) minimum concentration (Cmin) for divalproex-ER q12h was higher than the once-daily divalproex-ER Cmin (P=0.043). Once-daily divalproex-ER Cmin values were not different from those for divalproex q6h, suggesting that adequate trough steady-state concentrations are maintained with once daily dosing, despite enzyme-inducing comedication. The degree of peak-trough fluctuation (DFL, calculated as (Cmax-Cmin)/Cavg) in VPA concentration was less with both q12h (35.2% less) and once-daily (16.9% less) divalproex-ER regimens compared with q6h divalproex (P0.024). The DFL for divalproex-ER dosed as a q12h regimen was 22% less than that for once-daily divalproex-ER (P=0.02). The DFL in VPA concentration with divalproex-ER can be minimized with once-daily administration and more so with q12h administration, compared with conventional enteric-coated divalproex taken q6h.
    Epilepsy & Behavior 04/2006; 8(2):391-6. · 2.06 Impact Factor
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    ABSTRACT: Defining a quantitative and reliable relationship between in vitro drug release and in vivo absorption is highly desired for rational development, optimization, and evaluation of controlled-release dosage forms and manufacturing process. During the development of a once-daily extended-release (ER) tablet of divalproex sodium, a predictive in vitro drug release method was designed and statistically evaluated using three formulations with varying release rates. In order to establish an internally and externally validated Level A IVIVC, a total of five different ER formulations of divalproex sodium were used to evaluate a linear IVIVC model based on the in vitro test method. For internal validation, a single-dose four-way crossover study (N = 16) was performed using fast-, medium-, and slow-releasing ER formulations and a 12-h IV infusion of valproic acid as reference. To validate the IVIVC externally, a second three-way crossover study (N = 36) was performed using slightly-fast-, medium-, and slightly-slow-releasing ER formulations. The in vivo absorption-time profile was inferred by deconvolution of the observed plasma concentration-time profiles against the unit disposition function (UDF). A linear IVIVC model was established in which the in vivo absorption was expressed as a function of in vitro drug release. Plasma profiles of ER formulations were estimated via convolution of in vitro release profiles with the UDF. Successful internal and external validations of the model were demonstrated by individual and average absolute percent prediction errors of </=9% for both C(max) and AUC(infinity). In conclusion, a Level A IVIVC describing the entire time-course of plasma concentrations was developed and validated, both internally and externally, for ER formulations of divalproex sodium.
    Journal of Pharmaceutical Sciences 10/2005; 94(9):1949-56. · 3.13 Impact Factor
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    ABSTRACT: Levothyroxine (LT4) has a narrow therapeutic index. Consequently, precise standards for assessing the bioequivalence of different LT4 products are vital. We examined the methodology that the Food and Drug Administration (FDA) recommends for comparing the bioavailability of LT4 products, as well as three modifications to correct for endogenous, thyroxine (T4) levels, to determine if the methodology could distinguish LT4 products that differ by 12.5%, 25%, or 33%. With no baseline correction for the endogenous T4 pool, differences in administered LT4 doses that differed by 25%-33% could not be detected (450 microg and 400 microg doses versus 600 microg dose, respectively). The three mathematical correction methods could distinguish the doses that differed by 25% and 33%. None of the correction methods could distinguish dosage strengths that differed by 12.5% (450 microg versus 400 microg). Dose differences within this range are known to result in clinically relevant differences in safety and effectiveness. Methods of analysis of bioequivalence data that do not consider endogenous T4 concentrations confound accurate quantitation and interpretation of LT4 bioavailability. As a result, products inappropriately deemed bioequivalent may put patients at risk for iatrogenic hyperthyroidism or hypothyroidism. More precise methods for defining bioequivalence are required in order to ensure that LT4 products accepted as bioequivalent will perform equivalently in patients without the need for further monitoring and retitration of their dose.
    Thyroid 04/2004; 14(3):191-200. · 3.54 Impact Factor
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    ABSTRACT: Valproic acid (VPA) has a narrow therapeutic range (50-100mg/l) and exhibits nonlinear protein binding. Additionally, VPA pharmacokinetics are dependent on age, induction status, and formulation; so titration and dosing vary between individuals. The aim of these simulations was to determine optimal intravenous (i.v.) loading dose, and i.v. and oral VPA maintenance regimens. A 5-min 15mg/kg loading dose resulted in total and free plasma VPA concentrations of approximately 65 and 7.5mg/l in children, and approximately 80 and 11mg/l in adults, 1h after the infusion; induction status had little effect. For uninduced children and adults, 7.5 and 3.5mg/kg q6h i.v. valproate sodium, initiated 6h after loading dose maintains therapeutic plasma VPA concentrations. The rapid decline of plasma VPA concentrations following an i.v. loading dose in combination with the delayed initial absorption of drug from delayed-release divalproex sodium tablets warrant beginning q12h oral maintenance regimens of delayed-release divalproex sodium within 2h of a loading dose in the uninduced population. Plasma VPA concentrations can be sustained in the therapeutic range using once-daily maintenance regimens of extended-release divalproex sodium tablets if initiated concurrently with i.v. loading dose in the uninduced population. A two-fold higher i.v. and oral maintenance regimen dose may be required in induced patients.
    Epilepsy Research 03/2003; 53(1-2):29-38. · 2.24 Impact Factor
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    ABSTRACT: The availability of an intravenous formulation now makes possible rapid administration of valproate (VPA) loading doses, but estimates of key VPA pharmacokinetic parameters in patients have limited the use of this approach. VPA disposition was characterized in 112 epilepsy patients, with or without enzyme inducing comedications, randomized to either 3.0 or 1.5mg/kg/min infusions of valproate sodium injection. Maximum dose was </=15mg/kg per infusion. Total and unbound plasma VPA concentrations were determined from blood samples obtained prior to and for 6h following the infusion. Analyses of covariance assessed the effect of induction, weight, age, gender, albumin, creatinine, and infusion rate on pharmacokinetics. Maximum total and unbound VPA concentrations were 94 and 14mg/l, respectively. Total concentration fell below 50mg/l within 3h in induced and 6h in uninduced patients. VPA unbound fraction decreased from 15% at maximum concentration to 9% at 45mg/l. The mean (S.D.) distribution volume was 0.21 (0.044)l/kg. Induction status, albumin concentration, and infusion rate significantly affected pharmacokinetics. Measurement of unbound VPA may be useful when alterations in binding are suspected. Infusions up to 3mg/kg/min produce predictable total VPA concentrations when induction status and albumin levels are considered.
    Epilepsy Research 02/2003; 53(1-2):19-27. · 2.24 Impact Factor
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    ABSTRACT: The steady-state pharmacokinetics and pharmacodynamics of two oral doses of lopinavir-ritonavir (lopinavir/r; 400/100 and 533/133 mg) twice daily (BID) when dosed in combination with efavirenz, plus two nucleoside reverse transcriptase inhibitors, were assessed in a phase II, open-label, randomized, parallel arm study in 57 multiple protease inhibitor-experienced but non-nucleoside reverse transcriptase inhibitor-naive human immunodeficiency virus (HIV)-infected subjects. All subjects began dosing of lopinavir/r at 400/100 mg BID; subjects in one arm increased the lopinavir/r dose to 533/133 mg BID on day 14. When codosed with efavirenz, the lopinavir/r 400/100 mg BID regimen resulted in lower lopinavir concentrations in plasma, particularly C(min), than were observed in previous studies of lopinavir/r administered without efavirenz. Increasing the lopinavir/r dose to 533/133 mg increased the lopinavir area under the concentration-time curve over a 12-h dosing interval (AUC(12)), C(predose), and C(min) by 46, 70, and 141%, respectively. The increase in lopinavir C(max) (33%,) did not reach statistical significance. Ritonavir AUC(12), C(max), C(predose), and C(min) values were increased 46 to 63%. The lopinavir predose concentrations achieved with the 533/133-mg BID dose were similar to those observed with lopinavir/r 400/100 mg BID in the absence of efavirenz. Results from univariate logistic regression analyses identified lopinavir and efavirenz inhibitory quotient (IQ) parameters, as well as the baseline lopinavir phenotypic susceptibility, as predictors of antiviral response (HIV RNA < 400 copies/ml at week 24); however, no lopinavir or efavirenz concentration parameter was identified as a predictor. Multiple stepwise logistic regressions confirmed the significance of the IQ parameters, as well as other baseline characteristics, in predicting virologic response at 24 weeks in this patient population.
    Antimicrobial Agents and Chemotherapy 01/2003; 47(1):350-9. · 4.57 Impact Factor
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    ABSTRACT: Selective alpha1a-adrenoreceptor antagonists are effective agents for treatment of benign prostatic hyperplasia, a disorder occurring in middle-aged and elderly males. The objective of this study was to determine the single- and multiple-dose pharmacokinetics of fiduxosin, a novel, selective alpha1a-adrenoreceptor antagonist. This was a Phase I, randomized, double-blind, placebo-controlled, parallel-group, single and multiple oral dose study of fiduxosin. Single daily oral doses of 30, 60, or 90 mg of fiduxosin or placebo were administered to healthy adult male subjects (N = 36; 8 active and 4 placebo per dosing group) on Day 1 and Days 5 to 11 (7 consecutive days) after a high-fat breakfast. Fiduxosin plasma concentration-time profiles for Days 1 and 11 were used to assess fiduxosin pharmacokinetics. Fiduxosin single-dose and steady-state pharmacokinetics were dose independent after oral administration under nonfasting conditions. Steady state was achieved after 4 days of qd dosing. Approximately 28% of the oral dose was eliminated by the fecal route as unchanged drug. Less than 1% of the unchanged drug was recovered in the urine after oral administration.
    The Journal of Clinical Pharmacology 06/2002; 42(5):540-6. · 2.84 Impact Factor
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    ABSTRACT: Selective alpha1a-adrenoceptor antagonists are effective agents for treatment of benign prostatic hyperplasia, a disorder occurring in middle-aged and elderly males. The objective of this study was to determine the pharmacokinetics of fiduxosin, a novel alpha1a-adrenoceptor antagonist, following multiple dose administration. This was carried out in a Phase I, randomized, double-blind, placebo-controlled, parallel group, multiple oral dose study of fiduxosin. Single once-daily oral doses of 30, 60, 90 or 120 mg of fiduxosin or placebo were administered to healthy elderly male subjects (n = 48; 8 active and 4 placebo per dosing group) for 14 consecutive days. Fiduxosin plasma concentration-versus-time profiles for days 1, 7 and 14 were used to assess fiduxosin pharmacokinetics. Steady state was achieved by day 7. At steady-state mean Tmax (time to maximum plasma concentration), CL/F (apparent oral clearance) and Vbeta/F (apparent volume of distribution) ranges were 1.8-7.8 h, 27.3-47.2 L h(-1) and 846-1399 L, respectively. Tmax and VbetaF were independent of dose. Cmax (maximum plasma concentration), Cmin (minimum plasma concentration) and AUC24 (area under plasma concentration vs time curve from 0 to 24 h) for days 7 and 14 were linearly proportional with dose overthe 30-120 mg/day dose range and were unchanged from day 7 to day 14. It was concluded that fiduxosin multiple-dose pharmacokinetics were dose-independent and time-invariant over the 30-120 mg/day dose range under fasting conditions.
    Journal of Pharmacy and Pharmacology 06/2002; 54(5):641-7. · 2.03 Impact Factor
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    ABSTRACT: The effect of food on the pharmacokinetics of fiduxosin, a novel selective alpha1a-receptor antagonist, was determined in healthy male subjects. This was a Phase I, open-label, single-center, randomized, two-period, crossover, single oral dose study of fiduxosin. Healthy male subjects (N= 14) were administered single oral doses of 30 mg of fiduxosin under fasting or nonfasting (1026 Kcal, 54 g fat, 46% calories from fat) conditions in each period. Fiduxosin plasma concentration profiles were used to assess fiduxosin pharmacokinetics. The mean Cmax, Tmax, AUC(infinity), CL/F and Vbeta/F values under fasting and nonfasting conditions were 34.3 and 150 ng/mL, 5.4 and 5.4 h, 822 and 1940 ng x h/mL, 42.5 and 17.2 L/h, and 924 and 235 L, respectively. The harmonic mean t 1/2 under fasting and nonfasting conditions were 13.9 and 9.28 h, respectively. Food significantly increased the bioavailability of fiduxosin. Under the nonfasting regimen, the Cmax central value was more than 4-fold and the AUC(infinity) central value more than 2-fold the central value of the fasting regimen. Tmax was not significantly different between fasting and nonfasting regimens. Food also decreased fiduxosin oral clearance (CL/F) by 60% and volume of distribution (Vbeta/F) by 75%.
    European Journal of Drug Metabolism and Pharmacokinetics 01/2002; 27(1):49-52. · 1.31 Impact Factor
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    ABSTRACT: The pharmacokinetics of 1, 10, 23.25, and 139.5 mg doses of atrasentan was assessed in a placebo-controlled, double-blind, single oral dose study in 24 healthy male subjects. Atrasentan was well tolerated. Atrasentan pharmacokinetics was linear in the 1 to 23.25 mg dose range, with some dose dependency in the highest dose group. Harmonic mean terminal half-life was similar across all dose groups (20-25 h). Apparent oral clearance was low (12 L/h) for the highest dose group compared with the other three dose groups (21-27 L/h). The apparent volume of distribution was large (approximately 6 L/kg), consistent with extensive tissue distribution.
    The Journal of Clinical Pharmacology 05/2001; 41(4):397-403. · 2.84 Impact Factor
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    ABSTRACT: Objective: To determine the single- and multiple-dose pharmacokinetics of atrasentan, a highly selective endothelin-A receptor antagonist that is currently being investigated for the treatment of prostate cancer and cardiovascular disorders.Design: Phase I, randomised, placebo-controlled, double-blind, single- and multiple-dose study of orally administered atrasentan.Methods: Single daily oral doses of 1, 5, 10, 15, 20, 25, 30 or 40mg of atrasentan or placebo were administered to healthy male volunteers (n = 72; six active and three placebo per drug administration group) on study day 1 and days 3 to 9. Atrasentan plasma concentration-time profiles for day 1 and day 9 were used to assess atrasentan pharmacokinetics.Results: Except for the 1mg group, atrasentan plasma concentrations increased rapidly after single and multiple administration, declining thereafter biexponentially with a study-wide harmonic mean (pseudo-SD) half-life of 21 (12) hours and mean (SD) apparent total body clearance (CL/F) of 28 (9.8) L/h. For the 1mg group, there was no apparent distribution phase and the absorption was slower. Drug administration in the 40mg group was discontinued prematurely because of adverse events. Except for lower-than-predicted maximum plasma concentration (C) values for the 1mg group, drug exposure (C, trough concentration and area under the concentration-time curve) increased linearly with dose, and CL/F values were similar across groups, after single- and multiple-dose administration. Steady state was reached within 4 days of drug administration.Conclusion: The pharmacokinetics of atrasentan are dose- and time-independent after single- and multiple-dose administration over the range of 1 to 30 mg/day.
    Clinical Drug Investigation 01/2001; 21(2):129-136. · 1.70 Impact Factor
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    ABSTRACT: ABT-378 is a potent in vitro inhibitor of the HIV protease and is currently being developed for coadministration with another HIV protease inhibitor, ritonavir, as an oral therapeutic treatment for HIV infection. In the present study, the effect of ritonavir, a potent inhibitor of cytochrome P-450 (CYP) 3A, on the in vitro metabolism of ABT-378 was examined. Furthermore, the effect of ABT-378-ritonavir combinations on several CYP-dependent monooxygenase activities in human liver microsomes was also examined. ABT-378 was found to undergo NADPH- and CYP3A4/5-dependent metabolism to three major metabolites, M-1 (4-oxo) and M-3/M-4 (4-hydroxy epimers), as well as several minor oxidative metabolites in human liver microsomes. The mean apparent K(m) and V(max) values for the metabolism of ABT-378 by human liver microsomes were 6.8 +/- 3.6 microM and 9.4 +/- 5.5 nmol of ABT-378 metabolized/mg protein/min, respectively. Ritonavir inhibited human liver microsomal metabolism of ABT-378 potently (K(i) = 0.013 microM). The combination of ABT-378 and ritonavir was much weaker in inhibiting CYP-mediated biotransformations than ritonavir alone, and the inhibitory effect appears to be primarily due to the ritonavir component of the combination. The ABT-378-ritonavir combinations (at 3:1 and 29:1 ratios) inhibited CYP3A (IC(50) = 1.1 and 4.6 microM), albeit less potently than ritonavir (IC(50) = 0.14 microM). Metabolic reactions mediated by CYP1A2, CYP2A6, and CYP2E1 were not affected by the ABT-378-ritonavir combinations. The inhibitory effects of ABT-378-ritonavir combinations on CYP2B6 (IC(50) = >30 microM), CYP2C9 (IC(50) = 13.7 and 23.0 microM), CYP2C19 (IC(50) = 28.7 and 38.0 microM), and CYP2D6 (IC(50) = 13.5 and 29.0 microM) were marginal and are not likely to produce clinically significant drug-drug interactions.
    Drug Metabolism and Disposition 09/1999; 27(8):902-8. · 3.36 Impact Factor
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    ABSTRACT: The valine at position 82 (Val 82) in the active site of the human immunodeficiency virus (HIV) protease mutates in response to therapy with the protease inhibitor ritonavir. By using the X-ray crystal structure of the complex of HIV protease and ritonavir, the potent protease inhibitor ABT-378, which has a diminished interaction with Val 82, was designed. ABT-378 potently inhibited wild-type and mutant HIV protease (Ki = 1.3 to 3.6 pM), blocked the replication of laboratory and clinical strains of HIV type 1 (50% effective concentration [EC50], 0.006 to 0.017 microM), and maintained high potency against mutant HIV selected by ritonavir in vivo (EC50, </=0. 06 microM). The metabolism of ABT-378 was strongly inhibited by ritonavir in vitro. Consequently, following concomitant oral administration of ABT-378 and ritonavir, the concentrations of ABT-378 in rat, dog, and monkey plasma exceeded the in vitro antiviral EC50 in the presence of human serum by >50-fold after 8 h. In healthy human volunteers, coadministration of a single 400-mg dose of ABT-378 with 50 mg of ritonavir enhanced the area under the concentration curve of ABT-378 in plasma by 77-fold over that observed after dosing with ABT-378 alone, and mean concentrations of ABT-378 exceeded the EC50 for >24 h. These results demonstrate the potential utility of ABT-378 as a therapeutic intervention against AIDS.
    Antimicrobial Agents and Chemotherapy 01/1999; 42(12):3218-24. · 4.57 Impact Factor
  • S L Wong, G R Granneman
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    ABSTRACT: The pharmacokinetics of sertindole were studied in young, healthy volunteers after single and multiple oral dose administered under an escalating manner. In a low-dose study (study 1), subjects received 4-8 mg with a maintenance dose period of 7 days. In a high-dose study (study 2), subjects received 4 mg daily for 2 days, and the dose was increased by 4 mg increments every third day until reaching 20 mg daily. The mean terminal t 1,2 was 73 h after the final 8 mg dose in study 1 and 60 h after the 20 mg dose in study 2. The terminal elimination phase appeared to be monophasic in all the study subjects, suggesting that Michaelis-Menten saturable metabolism was not involved in the elimination of sertindole. Compartmental analyses suggested that the disproportional increase of the Cmax and AUC values from 4 mg to 20 mg during multiple dosing may be explained by saturable presystemic elimination of sertindole, leading to a higher fraction of sertindole available for absorption at higher doses.
    Journal of Pharmaceutical Sciences 01/1999; 87(12):1629-31. · 3.13 Impact Factor
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    ABSTRACT: The potential interaction between fluoxetine, a known inhibitor of cytochrome P-450 isoform 2D6 (CYP2D6), and ritonavir, a human immunodeficiency virus type 1 protease inhibitor, was evaluated in this open-label study. Sixteen male and female subjects ranging in age from 18 to 40 years completed the study. Subjects received single doses of 600 mg of ritonavir on days 1 and 10. On study days 3 to 10, all subjects received 30 mg of fluoxetine every 12 h for a total of 16 consecutive doses. Serial blood samples for determination of ritonavir concentrations in plasma were collected after the administration of ritonavir on days 1 and 10. A limited number of blood samples for determination of fluoxetine and norfluoxetine concentrations were collected after administration of the morning dose on day 10. A statistically significant increase (19%) in the ritonavir area under the concentration-time curve (AUC) was observed with concomitant fluoxetine administration, with individual changes ranging from -12 to +56%. The change in the ritonavir AUC with concomitant fluoxetine administration was positively correlated with the norfluoxetine 24-h AUC (AUC24) (r2 = 0.42), the norfluoxetine/fluoxetine AUC24 ratio (r2 = 0.53), and the fluoxetine elimination rate constant (r2 = 0.65), with larger increases in the ritonavir AUC tending to occur with higher norfluoxetine concentrations and higher fluoxetine elimination rate constants. The effect of fluoxetine appeared to be larger in subjects with the CYP2D6 wt/wt genotype. There was little or no effect on the time to maximum drug concentration (Cmax) in serum, Cmax, and the elimination rate constant of ritonavir with concomitant fluoxetine administration. Considering the magnitude of the change observed, no ritonavir dose adjustment is recommended during concomitant fluoxetine administration.
    Antimicrobial Agents and Chemotherapy 01/1999; 42(12):3107-12. · 4.57 Impact Factor
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    ABSTRACT: The pharmacokinetic interaction between indinavir and ritonavir was evaluated in five groups of healthy adult volunteers to explore the potential for twice-daily (b.i.d.) dosing of this combination. All subjects received 800 mg of indinavir every 8 h (q8h) on day 2. In addition, subjects in group I received one dose of 800 mg of indinavir on day 1 and 800 mg of indinavir q8h on day 17. Subjects in Groups II and IV each received one dose of 600 mg of indinavir on days 1 and 17, and subjects in groups III and V each received one dose of 400 mg of indinavir on days 1 and 17. During days 3 to 17, ritonavir placebo or ritonavir at 200, 300, 300, or 400 mg q12h was given to groups I, II, III, IV, and V, respectively. Ritonavir at steady state probably inhibited the cytochrome P-450 3A metabolism of indinavir and substantially increased plasma indinavir concentrations, with the area under the plasma concentration-time curve (AUC) increasing up to 475% and the peak concentration in serum (Cmax) increasing up to 110%. The Cmax/trough concentration ratio decreased from 50 in standard q8h regimens to less than 14 when indinavir was administered with ritonavir. For a constant indinavir dose, an increase in the ritonavir dose yielded similar indinavir AUCs, Cmaxs, and concentrations at 12 h (C12s). For a constant ritonavir dose, an increase in the indinavir dose resulted in approximately proportional increases in the indinavir AUC, less than proportional increases in Cmax, and slightly more than proportional increases in C12. Ritonavir reduced between-subject variability in the indinavir AUC and trough concentrations and did not affect indinavir renal clearance. With the altered pharmacokinetic profile, indinavir likely could be given as a b.i.d. combination regimen with ritonavir. This could potentially improve patient compliance and thereby reduce treatment failures.
    Antimicrobial Agents and Chemotherapy 12/1998; 42(11):2784-91. · 4.57 Impact Factor
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    A Hsu, G R Granneman, R J Bertz
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    ABSTRACT: Ritonavir is 1 of the 4 potent synthetic HIV protease inhibitors, approved by the US Food and Drug Administration (FDA) between 1995 and 1997, that have revolutionised HIV therapy. The extent of oral absorption is high and is not affected by food. Within the clinical concentration range, ritonavir is approximately 98 to 99% bound to plasma proteins, including albumin and alpha 1-acid glycoprotein. Cerebrospinal fluid (CSF) drug concentrations are low in relation to total plasma concentration. However, parallel decreases in the viral burden have been observed in the plasma, CSF and other tissues. Ritonavir is primarily metabolised by cytochrome P450 (CYP) 3A isozymes and, to a lesser extent, by CYP2D6. Four major oxidative metabolites have been identified in humans, but are unlikely to contribute to the antiviral effect. About 34% and 3.5% of a 600 mg dose is excreted as unchanged drug in the faeces and urine, respectively. The clinically relevant t1/2 beta is about 3 to 5 hours. Because of autoinduction, plasma concentrations generally reach steady state 2 weeks after the start of administration. The pharmacokinetics of ritonavir are relatively linear after multiple doses, with apparent oral clearance averaging 7 to 9 L/h. In vitro, ritonavir is a potent inhibitor of CYP3A. In vivo, ritonavir significantly increases the AUC of drugs primarily eliminated by CYP3A metabolism (e.g. clarithromycin, ketoconazole, rifabutin, and other HIV protease inhibitors, including indinavir, saquinavir and nelfinavir) with effects ranging from an increase of 77% to 20-fold in humans. It also inhibits CYP2D6-mediated metabolism, but to a significantly lesser extent (145% increase in desipramine AUC). Since ritonavir is also an inducer of several metabolising enzymes [CYP1A4, glucuronosyl transferase (GT), and possibly CYP2C9 and CYP2C19], the magnitude of drug interactions is difficult to predict, particularly for drugs that are metabolised by multiple enzymes or have low intrinsic clearance by CYP3A. For example, the AUC of CYP3A substrate methadone was slightly decreased and alprazolam was unaffected. Ritonavir is minimally affected by other CYP3A inhibitors, including ketoconazole. Rifampicin (rifampin), a potent CYP3A inducer, decreased the AUC of ritonavir by only 35%. The degree and duration of suppression of HIV replication is significantly correlated with the plasma concentrations. Thus, the large increase in the plasma concentrations of other protease inhibitors when coadministered with ritonavir forms the basis of rational dual protease inhibitor regimens, providing patients with 2 potent drugs at significantly reduced doses and less frequent dosage intervals. Combination treatment of ritonavir with saquinavir and indinavir results in potent and sustained clinical activity. Other important factors with combination regimens include reduced interpatient variability for high clearance agents, and elimination of the food effect on the bioavailibility of indinavir.
    Clinical Pharmacokinetics 11/1998; 35(4):275-91. · 5.49 Impact Factor
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    ABSTRACT: Background: Because ritonavir, a human immunodeficiency virus (HIV) protease inhibitor, and clarithromycin, a macrolide antibiotic used in the treatment of disseminated infection caused by Mycobacterium avium complex, are likely to be administered concurrently for treatment of patients with HIV and acquired immunodeficiency syndrome (AIDS), the drug interaction potential of these 2 agents was evaluated. Both clarithromycin and ritonavir are metabolized to a significant extent through cytochrome P450-mediated biotransformation and are potential inhibitors of these enzymes.Objective: To evaluate the pharmacokinetic effects of concomitant administration of multiple doses of ritonavir and clarithromycin.Methods: This was an open-label, randomized, 3-period crossover study. Ritonavir alone (200 mg every 8 hours), clarithromycin alone (500 mg every 12 hours), and ritonavir and clarithromycin in combination were administered to 22 healthy volunteers. Blood samples were collected on day 4 for determination of ritonavir, clarithromycin, and its metabolite 14-(R)-hydroxyclarithromycin.Results: Ritonavir practically completely inhibited the formation of 14-(R)-hydroxyclarithromycin. The mean area under the plasma concentration-time curve (AUC) for clarithromycin increased by 77%with concomitant ritonavir, and the harmonic mean terminal half-life increased from 5 hours to 14 hours. Statistically significant increases in peak plasma concentration (31%) and minimum plasma concentration (182%) were also observed. The effect of concomitant clarithromycin administration on ritonavir pharmacokinetics was statistically significant but small, with a 12.5%increase in mean AUC and a 15.3%increase in peak plasma concentration. The terminal half-life increased from 3.47 to 3.87 hours with concomitant clarithromycin.Conclusions: No adjustment of the ritonavir dose is necessary when administered with clarithromycin. In addition, no changes in clarithromycin dose are warranted in patients with normal renal function.
    Clinical Pharmacology &#38 Therapeutics 09/1998; 64(4):355-362. · 6.85 Impact Factor
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    ABSTRACT: To assess the effects of the protease inhibitor ritonavir on the pharmacokinetics of ethinyl oestradiol in healthy female volunteers. This was an open-label, single centre study in 23 subjects who received two single doses of oral contraceptive containing 50 microg ethinyl oestradiol on Day 1 (alone) and on Day 29 during concomitant ritonavir. Each subject received 16 days of every 12 h doses of ritonavir from Day 15 through Day 30. Blood samples were collected for serum ethinyl oestradiol concentrations for 48 h after each dose and for plasma ritonavir on Day 29 at 0 and 4 h postdose. Statistically significant decreases in ethinyl oestradiol mean Cmax (-32%) and mean AUC (-41%), and a statistically significant increase in the mean terminal elimination rate constant (+31%) were observed during concomitant ritonavir. The harmonic mean terminal half-life decreased from 17 h to 13 h during concomitant ritonavir. No statistically significant change was noted in tmax. The ratios of means (95% confidence intervals) for Cmax and AUC were 0.682 (0.612-0.758) and 0.595 (0.506-0.694), respectively. The changes in ethinyl oestradiol pharmacokinetics were consistent with an increase in clearance from enzymatic induction of glucuronidation and/or cytochrome P450 hydroxylation. Mean steady-state ritonavir concentrations of 6.5 and 13.4 microg ml(-1) were observed at 0 and 4 h postdose, respectively. Considering the extent of the decrease in ethinyl oestradiol concentrations, the use of alternate contraceptive measures should be considered when ritonavir is being administered.
    British Journal of Clinical Pharmacology 09/1998; 46(2):111-6. · 3.69 Impact Factor
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    ABSTRACT: In two open-label long-term safety studies, we determined tiagabine (TGB) pharmacokinetics in patients with epilepsy. In all, 2,147 plasma samples from 511 patients who participated in the studies were available. The total daily dose ranged from 2 mg administered once daily to 80 mg administered in four doses. A one-compartment model with first-order absorption and elimination was used to fit the TGB plasma concentration-time data, with a population pharmacokinetic approach. The patients' average (+/-SD) weight and age were 73.8+/-20.7 kg and 32.1+/-12.3 years. The most significantly factor affecting TGB pharmacokinetics was concomitant administration of other antiepileptic drugs (AEDs). The central clearance value in patients receiving AEDs known to induce hepatic drug metabolism was 21.4 L/h, a value 67% higher than the central clearance estimate obtained for the patients receiving AEDs not known to affect hepatic drug metabolism (12.8 L/h). There was no evidence of any dose or time effect, indicating that TGB pharmacokinetics are linear. TGB pharmacokinetics were not different in white, black, or Hispanic patients, although our ability to explore racial effects was limited since 90% of the patients were white. No other demographic variables (including age and smoking) or any clinical chemistry measurements (including bilirubin, SGOT, and SGPT) were important in explaining the variability in the clearance estimates. TGB pharmacokinetics are linear, influenced by enzyme-inducing AEDs, and largely unaffected by other demographic variables.
    Epilepsia 09/1998; 39(8):868-73. · 3.91 Impact Factor

Publication Stats

3k Citations
440.40 Total Impact Points

Institutions

  • 1987–2006
    • Abbott Laboratories
      • • Global Pharmaceutical Research and Development
      • • Abbott Laboratories
      North Chicago, IL, United States
  • 2003
    • University of Minnesota Twin Cities
      • College of Pharmacy
      Minneapolis, MN, United States
  • 1992
    • Institute For Biomedical And Pharmaceutical Research
      Nuremberg, Bavaria, Germany
  • 1991
    • Drug Safety Research Unit
      Southampton, England, United Kingdom