The disposition kinetics of acetazolamide (AZ) has been studied in four young and four elderly he... more The disposition kinetics of acetazolamide (AZ) has been studied in four young and four elderly healthy volunteers, each of whom received an intravenous bolus dose of 5 mg/kg. The concentration time profile of AZ was determined in plasma, plasma ultrafiltrate, erythrocytes and urine. 2 While the mean area under unbound plasma concentration-time curves was 81% higher in elderly subjects, areas based on total drug concentrations were similar in both groups. The mean renal plasma clearance was similar in both groups. The mean renal plasma clearance was similar between young and old for total AZ, but was significantly lower in the elderly for unbound drug (8.88 ml min-' kg-' vs 15.7 ml min-' kg-'). Renal clearance of unbound AZ correlated well with creatinine clearance (r = 0.846, P < 0.01). 3 Peak erythrocyte levels were 45% higher in the elderly group (37.2 ,g/ml vs 25.3 jig/ml) and were paralleled by a 46% increase in the mean area under the erythrocyte concentration-time curve for this age group. The unbound fraction of AZ in plasma was significantly greater in elderly than younger subjects (6.9 vs 4.1%, P < 0.05). Integrated AZ erythrocyte concentrations correlated positively with AZ free fraction in plasma and inversely with its unbound renal clearance. These observed differences in AZ disposition between elderly and young have served to clarify host factors which may importantly influence susceptibility to adverse effects.
Ertugliflozin, a sodium‐glucose cotransporter 2 inhibitor, is primarily metabolized via glucuroni... more Ertugliflozin, a sodium‐glucose cotransporter 2 inhibitor, is primarily metabolized via glucuronidation by the uridine 5′‐diphospho‐glucuronosyltransferase (UGT) isoform UGT1A9. This noncompartmental meta‐analysis of ertugliflozin pharmacokinetics evaluated the relationship between ertugliflozin exposure and dose, and the effect of UGT1A9 genotype on ertugliflozin exposure. Pharmacokinetic data from 25 phase 1 studies were pooled. Structural models for dose proportionality described the relationship between ertugliflozin area under the plasma concentration‐time curve (AUC) or maximum observed plasma concentration (Cmax) and dose. A structural model for the UGT1A9 genotype described the relationship between ertugliflozin AUC and dose, with genotype information on 3 UGT1A9 polymorphisms (UGT1A9‐2152, UGT1A9*3, UGT1A9*1b) evaluated as covariates from the full model. Ertugliflozin AUC and Cmax increased in a dose‐proportional manner over the dose range of 0.5‐300 mg, and population‐pred...
The feasibility of monitoring cisplatin chemotherapy by measuring platinum (Pt) concentrations in... more The feasibility of monitoring cisplatin chemotherapy by measuring platinum (Pt) concentrations in blood mononuclear cells was tested in six patients (four with squamous cell carcinomas of the head and neck, one with non-Hodgkin's lymphoma, and one with lung carcinoma). Blood samples (20 to 40 mL) were collected at intervals from 6 min to 21 days after an iv infusion of cisplatin (80 or 100 mg per m2). Blood mononuclear cells were harvested on a Ficoll-Hypaque gradient, washed repeatedly, counted, and homogenized by sonication in 0.5 mL of saline solution. Pt was analyzed in duplicate 40 microL samples of plasma (N = 26) or cell homogenates (N = 23) by electrothermal atomic absorption spectrophotometry with Zeeman background correction. Immediately after the cisplatin infusion, plasma Pt concentrations averaged 2.6 (SD +/- 0.2) mg per L and mononuclear cell Pt concentrations averaged 2.5 +/- 0.5 ng per 10(6) cells. At 24 to 26 hr post-infusion, plasma Pt concentrations averaged 1...
The plasma concentration-time profile of acetazolamide (AZ) following an intravenous bolus dose (... more The plasma concentration-time profile of acetazolamide (AZ) following an intravenous bolus dose (5 mg kg-') was determined during control, aspirin and flurbiprofen (FLU) treatment periods. The unbound fraction of AZ in plasma increased three-fold in the presence of salicylate (SA) while, in contrast, FLU produced consistent, but statistically insignificant, increases in binding. SA caused a two-fold decrease in both unbound AZ renal clearance and apparent volume of distribution at steady-state, while FLU produced a small, but significant, increase only in the latter. The area under the concentration-time curve for AZ in erythrocytes was increased by about 40% during SA treatment while FLU had no effect. Our results suggest that on a pharmacokinetic basis FLU may be a safer nonsteroidal anti-inflammatory drug (NSAID) to co-administer with AZ.
The pharmacokinetics and bioavailability of ofloxacin in 20 healthy male volunteers were studied ... more The pharmacokinetics and bioavailability of ofloxacin in 20 healthy male volunteers were studied in an open-label, randomized, two-way crossover study. Ofloxacin (400 mg) was administered either as a 1-h infusion or as an oral tablet. The mean peak concentration after intravenous infusion was 4.30 +/- 0.69 microgram/ml, and that after oral administration was 3.14 +/- 0.53 microgram/ml, occurring 1.74 +/- 0.57 h after dosing. The bioavailability (F) of the oral dosage form of ofloxacin was virtually identical to that of the intravenous form (F = 105% +/- 7%). This complete bioavailability of ofloxacin is supportive of the use of the oral dosage form for the treatment of infections in hospitalized patients either as a replacement for intravenous ofloxacin therapy or in streamlining therapy from the intravenous to the oral route.
The penetration of multiple-dose concentrations of oral fleroxacin (400 mg every 24 h) and ciprof... more The penetration of multiple-dose concentrations of oral fleroxacin (400 mg every 24 h) and ciprofloxacin (500 mg every 12 h) into skin blister fluid in 12 healthy volunteers was determined in a randomized crossover study. Serum, blister fluid, and paper disk samples were analyzed by large-plate microbiologic assay. The mean areas under the concentration-time curve (AUC) for serum were 88.6 and 18.2 micrograms.h/ml/70 kg for fleroxacin and ciprofloxacin, respectively. The mean AUC for blister fluid and paper disks were 71.2 and 15.0 micrograms.h/ml/70 kg and 77.8 and 15.4 micrograms.h/ml/70 kg for fleroxacin and ciprofloxacin, respectively. Calculated penetration into interstitial fluid ranged from 74 to 92% for fleroxacin and 56 to 96% for ciprofloxacin; penetration was calculated by using the ratio of maximum drug concentration or AUC in blister fluid and paper disks to maximum drug concentration or AUC in serum. There was no significant difference between fleroxacin and ciprofloxa...
Background Accumulating evidence supports the role of the mineralocorticoid receptor (MR) in the ... more Background Accumulating evidence supports the role of the mineralocorticoid receptor (MR) in the pathogenesis of diabetic nephropathy. These findings have generated renewed interest in novel MR antagonists with improved selectivity against other nuclear hormone receptors and a potentially reduced risk of hyperkalemia. Characterization of novel MR antagonists warrants establishing translatable biomarkers of activity at the MR receptor. We assessed the translatability of urinary sodium to potassium ratio (Na+/K+) and plasma aldosterone as biomarkers of MR antagonism using eplerenone (Inspra®), a commercially available MR antagonist. Further we utilized these biomarkers to demonstrate antagonism of MR by PF-03882845, a novel compound. Methods The effect of eplerenone and PF-03882845 on urinary Na+/K+ and plasma aldosterone were characterized in Sprague-Dawley rats and spontaneously hypertensive rats (SHR). Additionally, the effect of eplerenone on these biomarkers was determined in hea...
Background Accumulating evidence supports the role of the mineralocorticoid receptor (MR) in the ... more Background Accumulating evidence supports the role of the mineralocorticoid receptor (MR) in the pathogenesis of diabetic nephropathy. These findings have generated renewed interest in novel MR antagonists with improved selectivity against other nuclear hormone receptors and a potentially reduced risk of hyperkalemia. Characterization of novel MR antagonists warrants establishing translatable biomarkers of activity at the MR receptor. We assessed the translatability of urinary sodium to potassium ratio (Na+/K+) and plasma aldosterone as biomarkers of MR antagonism using eplerenone (Inspra®), a commercially available MR antagonist. Further we utilized these biomarkers to demonstrate antagonism of MR by PF-03882845, a novel compound. Methods The effect of eplerenone and PF-03882845 on urinary Na+/K+ and plasma aldosterone were characterized in Sprague-Dawley rats and spontaneously hypertensive rats (SHR). Additionally, the effect of eplerenone on these biomarkers was determined in hea...
Purpose The objectives of this analysis were to characterize the population pharmacokinetics (PK)... more Purpose The objectives of this analysis were to characterize the population pharmacokinetics (PK) of PF-06439535 (a bevacizumab biosimilar) and reference bevacizumab (Avastin®) sourced from the European Union (bevacizumab-EU) in patients with advanced non-squamous non-small cell lung cancer (NSCLC), and to quantify the difference in PK parameters between the two drug products via covariate analysis. Methods Pooled PF-06439535 and bevacizumab-EU serum concentration data from a comparative clinical efficacy and safety study (NCT02364999) in patients with NSCLC (N = 719) were analyzed using a non-linear mixed-effects modeling approach. Patients received PF-06439535 plus chemotherapy or bevacizumab-EU plus chemotherapy every 21 days for 4–6 cycles, followed by monotherapy with PF-06439535 or bevacizumab-EU. PF-06439535 or bevacizumab-EU was administered intravenously at a dose of 15 mg/kg. Effects of patient and disease covariates, as well as the drug product (PF-06439535 versus bevaciz...
Quantification of in-vitro post-antibiotic effect based on the mean recovery-time. II: A comparis... more Quantification of in-vitro post-antibiotic effect based on the mean recovery-time. II: A comparison of colony counting versus photometric
Current opinion in drug discovery & development, 2007
The pharmacology of therapeutic monoclonal antibodies (mAbs) is complex and dependant on both the... more The pharmacology of therapeutic monoclonal antibodies (mAbs) is complex and dependant on both the structure of the antibody and the physiological system that it targets. Patient exposure and responses to mAbs are also related to the structure and activity of mAbs. Furthermore, the pharmacokinetics and pharmacodynamics of mAbs are often inter-related. Pharmacokinetic and pharmacodynamic modeling have been used to elucidate or support the mechanisms of antibodies in development and can be used to identify appropriate dose regimens. Consequently, pharmacokinetic and pharmacodynamic modeling often plays a larger role during the development of therapeutic mAbs than for small molecules.
Purpose: The CYP2E1 probe drug chlorzoxazone (CZ) is extensively metabolized to 6-OHchlorzoxazone... more Purpose: The CYP2E1 probe drug chlorzoxazone (CZ) is extensively metabolized to 6-OHchlorzoxazone (HCZ). The HCZ/CZ ratio is used as an index of CYP2E1 activity, but it is not valid in patients with kidney disease. Individual estimates of HCZ formation clearance (CLf) obtained via ...
Bococizumab is a humanized monoclonal antibody-binding proprotein convertase subtilisin/kexin typ... more Bococizumab is a humanized monoclonal antibody-binding proprotein convertase subtilisin/kexin type 9, which may be a potential therapeutic option for reducing low-density lipoprotein cholesterol (LDL-C) levels in patients with hypercholesterolemia. In this 24-week, multicenter, double-blind, placebo-controlled, dose-ranging study (NCT01592240), subjects with LDL-C levels ≥80 mg/dl on stable statin therapy were randomized to Q14 days subcutaneous placebo or bococizumab 50, 100, or 150 mg or Q28 days subcutaneous placebo or bococizumab 200 or 300 mg. Doses of bococizumab were reduced if LDL-C levels persistently decreased to ≤25 mg/dl. The primary end point was the absolute change in LDL-C levels from baseline to week 12 after placebo or bococizumab administration. Continuation of bococizumab administration through to week 24 enabled the collection of safety data over an extended period. Of the 354 subjects randomized, 351 received treatment (placebo [n = 100] or bococizumab [n = 251]...
Current opinion in drug discovery & development, 2007
The pharmacology of therapeutic monoclonal antibodies (mAbs) is complex and dependant on both the... more The pharmacology of therapeutic monoclonal antibodies (mAbs) is complex and dependant on both the structure of the antibody and the physiological system that it targets. Patient exposure and responses to mAbs are also related to the structure and activity of mAbs. Furthermore, the pharmacokinetics and pharmacodynamics of mAbs are often inter-related. Pharmacokinetic and pharmacodynamic modeling have been used to elucidate or support the mechanisms of antibodies in development and can be used to identify appropriate dose regimens. Consequently, pharmacokinetic and pharmacodynamic modeling often plays a larger role during the development of therapeutic mAbs than for small molecules.
Drug metabolism and disposition: the biological fate of chemicals, 1996
An isolated perfused rat kidney (IPK) technique was used to study the effect of salicylic acid (S... more An isolated perfused rat kidney (IPK) technique was used to study the effect of salicylic acid (SA) on the excretion of acetazolamide (AZ). Initial experiments were conducted in the absence of interactants at three nominal AZ concentrations (50, 100, and 250 micrograms/ml). Over the concentration range studied, AZ demonstrated net tubular secretion in the IPK. Significant decreases in excretion ratio (4.97 +/- 0.79-2.66 +/- 1.1) and secretory clearance (0.809 +/- 0.23-0.541 +/- 0.28) were observed with increasing AZ concentration, consistent with saturation of tubular secretion. Using a facilitated model for renal secretion, values of tubular transport parameters were obtained from a plot of excretion ratio vs. unbound AZ concentration: tmax = 118 +/- 29.4 micrograms/min, KM = 53.4 +/- 22.4 micrograms/ml, and tmax(A) = 6.31 +/- 2.82 micrograms/min. In the presence of SA (200 micrograms/ml), renal secretion of AZ was inhibited, as demonstrated by significant decreases in renal cleara...
The Journal of pharmacology and experimental therapeutics, 1995
The impact of albumin on the renal elimination of acetazolamide, a low extraction ratio compound,... more The impact of albumin on the renal elimination of acetazolamide, a low extraction ratio compound, was investigated in the isolated perfused rat kidney. Perfusion studies were conducted over a wide range of protein concentrations (0.25, 0.5, 0.75, 1.0, 4.0 and 6.0 g/100 ml) and an initial drug concentration of 100 micrograms/ml. Kidney viability was within normal limits among all treatment groups. Over the range of albumin levels studied, an approximate 3.4-fold increase in drug-free fraction effected a 2.8-fold increase in renal clearance. Although this finding contradicted conventional wisdom regarding extraction ratio and renal elimination, the results were consistent with a proposed ancillary role of albumin in renal tubular transport processes. An alternative clearance model was developed, analogous to earlier models of hepatic elimination. The facilitated renal clearance model utilized and validated in this investigation represents a composite of previously proposed theories, m...
Purpose: It may be important to understand time-dependencies in ECG data when developing models a... more Purpose: It may be important to understand time-dependencies in ECG data when developing models as a function of drug concentration in longitudinal studies. A model-based analysis was employed to explore and compare the dependence of RR, QT and QTcI (individual rate-corrected QT) on daytime temporal fluctuations.Methods: Data were collected from normal, healthy volunteers (32 subjects, 4 occasions). Intercept (mean) and
The disposition kinetics of acetazolamide (AZ) has been studied in four young and four elderly he... more The disposition kinetics of acetazolamide (AZ) has been studied in four young and four elderly healthy volunteers, each of whom received an intravenous bolus dose of 5 mg/kg. The concentration time profile of AZ was determined in plasma, plasma ultrafiltrate, erythrocytes and urine. 2 While the mean area under unbound plasma concentration-time curves was 81% higher in elderly subjects, areas based on total drug concentrations were similar in both groups. The mean renal plasma clearance was similar in both groups. The mean renal plasma clearance was similar between young and old for total AZ, but was significantly lower in the elderly for unbound drug (8.88 ml min-' kg-' vs 15.7 ml min-' kg-'). Renal clearance of unbound AZ correlated well with creatinine clearance (r = 0.846, P < 0.01). 3 Peak erythrocyte levels were 45% higher in the elderly group (37.2 ,g/ml vs 25.3 jig/ml) and were paralleled by a 46% increase in the mean area under the erythrocyte concentration-time curve for this age group. The unbound fraction of AZ in plasma was significantly greater in elderly than younger subjects (6.9 vs 4.1%, P < 0.05). Integrated AZ erythrocyte concentrations correlated positively with AZ free fraction in plasma and inversely with its unbound renal clearance. These observed differences in AZ disposition between elderly and young have served to clarify host factors which may importantly influence susceptibility to adverse effects.
Ertugliflozin, a sodium‐glucose cotransporter 2 inhibitor, is primarily metabolized via glucuroni... more Ertugliflozin, a sodium‐glucose cotransporter 2 inhibitor, is primarily metabolized via glucuronidation by the uridine 5′‐diphospho‐glucuronosyltransferase (UGT) isoform UGT1A9. This noncompartmental meta‐analysis of ertugliflozin pharmacokinetics evaluated the relationship between ertugliflozin exposure and dose, and the effect of UGT1A9 genotype on ertugliflozin exposure. Pharmacokinetic data from 25 phase 1 studies were pooled. Structural models for dose proportionality described the relationship between ertugliflozin area under the plasma concentration‐time curve (AUC) or maximum observed plasma concentration (Cmax) and dose. A structural model for the UGT1A9 genotype described the relationship between ertugliflozin AUC and dose, with genotype information on 3 UGT1A9 polymorphisms (UGT1A9‐2152, UGT1A9*3, UGT1A9*1b) evaluated as covariates from the full model. Ertugliflozin AUC and Cmax increased in a dose‐proportional manner over the dose range of 0.5‐300 mg, and population‐pred...
The feasibility of monitoring cisplatin chemotherapy by measuring platinum (Pt) concentrations in... more The feasibility of monitoring cisplatin chemotherapy by measuring platinum (Pt) concentrations in blood mononuclear cells was tested in six patients (four with squamous cell carcinomas of the head and neck, one with non-Hodgkin's lymphoma, and one with lung carcinoma). Blood samples (20 to 40 mL) were collected at intervals from 6 min to 21 days after an iv infusion of cisplatin (80 or 100 mg per m2). Blood mononuclear cells were harvested on a Ficoll-Hypaque gradient, washed repeatedly, counted, and homogenized by sonication in 0.5 mL of saline solution. Pt was analyzed in duplicate 40 microL samples of plasma (N = 26) or cell homogenates (N = 23) by electrothermal atomic absorption spectrophotometry with Zeeman background correction. Immediately after the cisplatin infusion, plasma Pt concentrations averaged 2.6 (SD +/- 0.2) mg per L and mononuclear cell Pt concentrations averaged 2.5 +/- 0.5 ng per 10(6) cells. At 24 to 26 hr post-infusion, plasma Pt concentrations averaged 1...
The plasma concentration-time profile of acetazolamide (AZ) following an intravenous bolus dose (... more The plasma concentration-time profile of acetazolamide (AZ) following an intravenous bolus dose (5 mg kg-') was determined during control, aspirin and flurbiprofen (FLU) treatment periods. The unbound fraction of AZ in plasma increased three-fold in the presence of salicylate (SA) while, in contrast, FLU produced consistent, but statistically insignificant, increases in binding. SA caused a two-fold decrease in both unbound AZ renal clearance and apparent volume of distribution at steady-state, while FLU produced a small, but significant, increase only in the latter. The area under the concentration-time curve for AZ in erythrocytes was increased by about 40% during SA treatment while FLU had no effect. Our results suggest that on a pharmacokinetic basis FLU may be a safer nonsteroidal anti-inflammatory drug (NSAID) to co-administer with AZ.
The pharmacokinetics and bioavailability of ofloxacin in 20 healthy male volunteers were studied ... more The pharmacokinetics and bioavailability of ofloxacin in 20 healthy male volunteers were studied in an open-label, randomized, two-way crossover study. Ofloxacin (400 mg) was administered either as a 1-h infusion or as an oral tablet. The mean peak concentration after intravenous infusion was 4.30 +/- 0.69 microgram/ml, and that after oral administration was 3.14 +/- 0.53 microgram/ml, occurring 1.74 +/- 0.57 h after dosing. The bioavailability (F) of the oral dosage form of ofloxacin was virtually identical to that of the intravenous form (F = 105% +/- 7%). This complete bioavailability of ofloxacin is supportive of the use of the oral dosage form for the treatment of infections in hospitalized patients either as a replacement for intravenous ofloxacin therapy or in streamlining therapy from the intravenous to the oral route.
The penetration of multiple-dose concentrations of oral fleroxacin (400 mg every 24 h) and ciprof... more The penetration of multiple-dose concentrations of oral fleroxacin (400 mg every 24 h) and ciprofloxacin (500 mg every 12 h) into skin blister fluid in 12 healthy volunteers was determined in a randomized crossover study. Serum, blister fluid, and paper disk samples were analyzed by large-plate microbiologic assay. The mean areas under the concentration-time curve (AUC) for serum were 88.6 and 18.2 micrograms.h/ml/70 kg for fleroxacin and ciprofloxacin, respectively. The mean AUC for blister fluid and paper disks were 71.2 and 15.0 micrograms.h/ml/70 kg and 77.8 and 15.4 micrograms.h/ml/70 kg for fleroxacin and ciprofloxacin, respectively. Calculated penetration into interstitial fluid ranged from 74 to 92% for fleroxacin and 56 to 96% for ciprofloxacin; penetration was calculated by using the ratio of maximum drug concentration or AUC in blister fluid and paper disks to maximum drug concentration or AUC in serum. There was no significant difference between fleroxacin and ciprofloxa...
Background Accumulating evidence supports the role of the mineralocorticoid receptor (MR) in the ... more Background Accumulating evidence supports the role of the mineralocorticoid receptor (MR) in the pathogenesis of diabetic nephropathy. These findings have generated renewed interest in novel MR antagonists with improved selectivity against other nuclear hormone receptors and a potentially reduced risk of hyperkalemia. Characterization of novel MR antagonists warrants establishing translatable biomarkers of activity at the MR receptor. We assessed the translatability of urinary sodium to potassium ratio (Na+/K+) and plasma aldosterone as biomarkers of MR antagonism using eplerenone (Inspra®), a commercially available MR antagonist. Further we utilized these biomarkers to demonstrate antagonism of MR by PF-03882845, a novel compound. Methods The effect of eplerenone and PF-03882845 on urinary Na+/K+ and plasma aldosterone were characterized in Sprague-Dawley rats and spontaneously hypertensive rats (SHR). Additionally, the effect of eplerenone on these biomarkers was determined in hea...
Background Accumulating evidence supports the role of the mineralocorticoid receptor (MR) in the ... more Background Accumulating evidence supports the role of the mineralocorticoid receptor (MR) in the pathogenesis of diabetic nephropathy. These findings have generated renewed interest in novel MR antagonists with improved selectivity against other nuclear hormone receptors and a potentially reduced risk of hyperkalemia. Characterization of novel MR antagonists warrants establishing translatable biomarkers of activity at the MR receptor. We assessed the translatability of urinary sodium to potassium ratio (Na+/K+) and plasma aldosterone as biomarkers of MR antagonism using eplerenone (Inspra®), a commercially available MR antagonist. Further we utilized these biomarkers to demonstrate antagonism of MR by PF-03882845, a novel compound. Methods The effect of eplerenone and PF-03882845 on urinary Na+/K+ and plasma aldosterone were characterized in Sprague-Dawley rats and spontaneously hypertensive rats (SHR). Additionally, the effect of eplerenone on these biomarkers was determined in hea...
Purpose The objectives of this analysis were to characterize the population pharmacokinetics (PK)... more Purpose The objectives of this analysis were to characterize the population pharmacokinetics (PK) of PF-06439535 (a bevacizumab biosimilar) and reference bevacizumab (Avastin®) sourced from the European Union (bevacizumab-EU) in patients with advanced non-squamous non-small cell lung cancer (NSCLC), and to quantify the difference in PK parameters between the two drug products via covariate analysis. Methods Pooled PF-06439535 and bevacizumab-EU serum concentration data from a comparative clinical efficacy and safety study (NCT02364999) in patients with NSCLC (N = 719) were analyzed using a non-linear mixed-effects modeling approach. Patients received PF-06439535 plus chemotherapy or bevacizumab-EU plus chemotherapy every 21 days for 4–6 cycles, followed by monotherapy with PF-06439535 or bevacizumab-EU. PF-06439535 or bevacizumab-EU was administered intravenously at a dose of 15 mg/kg. Effects of patient and disease covariates, as well as the drug product (PF-06439535 versus bevaciz...
Quantification of in-vitro post-antibiotic effect based on the mean recovery-time. II: A comparis... more Quantification of in-vitro post-antibiotic effect based on the mean recovery-time. II: A comparison of colony counting versus photometric
Current opinion in drug discovery & development, 2007
The pharmacology of therapeutic monoclonal antibodies (mAbs) is complex and dependant on both the... more The pharmacology of therapeutic monoclonal antibodies (mAbs) is complex and dependant on both the structure of the antibody and the physiological system that it targets. Patient exposure and responses to mAbs are also related to the structure and activity of mAbs. Furthermore, the pharmacokinetics and pharmacodynamics of mAbs are often inter-related. Pharmacokinetic and pharmacodynamic modeling have been used to elucidate or support the mechanisms of antibodies in development and can be used to identify appropriate dose regimens. Consequently, pharmacokinetic and pharmacodynamic modeling often plays a larger role during the development of therapeutic mAbs than for small molecules.
Purpose: The CYP2E1 probe drug chlorzoxazone (CZ) is extensively metabolized to 6-OHchlorzoxazone... more Purpose: The CYP2E1 probe drug chlorzoxazone (CZ) is extensively metabolized to 6-OHchlorzoxazone (HCZ). The HCZ/CZ ratio is used as an index of CYP2E1 activity, but it is not valid in patients with kidney disease. Individual estimates of HCZ formation clearance (CLf) obtained via ...
Bococizumab is a humanized monoclonal antibody-binding proprotein convertase subtilisin/kexin typ... more Bococizumab is a humanized monoclonal antibody-binding proprotein convertase subtilisin/kexin type 9, which may be a potential therapeutic option for reducing low-density lipoprotein cholesterol (LDL-C) levels in patients with hypercholesterolemia. In this 24-week, multicenter, double-blind, placebo-controlled, dose-ranging study (NCT01592240), subjects with LDL-C levels ≥80 mg/dl on stable statin therapy were randomized to Q14 days subcutaneous placebo or bococizumab 50, 100, or 150 mg or Q28 days subcutaneous placebo or bococizumab 200 or 300 mg. Doses of bococizumab were reduced if LDL-C levels persistently decreased to ≤25 mg/dl. The primary end point was the absolute change in LDL-C levels from baseline to week 12 after placebo or bococizumab administration. Continuation of bococizumab administration through to week 24 enabled the collection of safety data over an extended period. Of the 354 subjects randomized, 351 received treatment (placebo [n = 100] or bococizumab [n = 251]...
Current opinion in drug discovery & development, 2007
The pharmacology of therapeutic monoclonal antibodies (mAbs) is complex and dependant on both the... more The pharmacology of therapeutic monoclonal antibodies (mAbs) is complex and dependant on both the structure of the antibody and the physiological system that it targets. Patient exposure and responses to mAbs are also related to the structure and activity of mAbs. Furthermore, the pharmacokinetics and pharmacodynamics of mAbs are often inter-related. Pharmacokinetic and pharmacodynamic modeling have been used to elucidate or support the mechanisms of antibodies in development and can be used to identify appropriate dose regimens. Consequently, pharmacokinetic and pharmacodynamic modeling often plays a larger role during the development of therapeutic mAbs than for small molecules.
Drug metabolism and disposition: the biological fate of chemicals, 1996
An isolated perfused rat kidney (IPK) technique was used to study the effect of salicylic acid (S... more An isolated perfused rat kidney (IPK) technique was used to study the effect of salicylic acid (SA) on the excretion of acetazolamide (AZ). Initial experiments were conducted in the absence of interactants at three nominal AZ concentrations (50, 100, and 250 micrograms/ml). Over the concentration range studied, AZ demonstrated net tubular secretion in the IPK. Significant decreases in excretion ratio (4.97 +/- 0.79-2.66 +/- 1.1) and secretory clearance (0.809 +/- 0.23-0.541 +/- 0.28) were observed with increasing AZ concentration, consistent with saturation of tubular secretion. Using a facilitated model for renal secretion, values of tubular transport parameters were obtained from a plot of excretion ratio vs. unbound AZ concentration: tmax = 118 +/- 29.4 micrograms/min, KM = 53.4 +/- 22.4 micrograms/ml, and tmax(A) = 6.31 +/- 2.82 micrograms/min. In the presence of SA (200 micrograms/ml), renal secretion of AZ was inhibited, as demonstrated by significant decreases in renal cleara...
The Journal of pharmacology and experimental therapeutics, 1995
The impact of albumin on the renal elimination of acetazolamide, a low extraction ratio compound,... more The impact of albumin on the renal elimination of acetazolamide, a low extraction ratio compound, was investigated in the isolated perfused rat kidney. Perfusion studies were conducted over a wide range of protein concentrations (0.25, 0.5, 0.75, 1.0, 4.0 and 6.0 g/100 ml) and an initial drug concentration of 100 micrograms/ml. Kidney viability was within normal limits among all treatment groups. Over the range of albumin levels studied, an approximate 3.4-fold increase in drug-free fraction effected a 2.8-fold increase in renal clearance. Although this finding contradicted conventional wisdom regarding extraction ratio and renal elimination, the results were consistent with a proposed ancillary role of albumin in renal tubular transport processes. An alternative clearance model was developed, analogous to earlier models of hepatic elimination. The facilitated renal clearance model utilized and validated in this investigation represents a composite of previously proposed theories, m...
Purpose: It may be important to understand time-dependencies in ECG data when developing models a... more Purpose: It may be important to understand time-dependencies in ECG data when developing models as a function of drug concentration in longitudinal studies. A model-based analysis was employed to explore and compare the dependence of RR, QT and QTcI (individual rate-corrected QT) on daytime temporal fluctuations.Methods: Data were collected from normal, healthy volunteers (32 subjects, 4 occasions). Intercept (mean) and
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