Stephen C. Olson

Erythromycin Coadministration Increases Plasma Atorvastatin Concentrations

The effect of erythromycin on the pharmacokinetics of atorvastatin, an inhibitor of HMG‐CoA reductase, was investigated in 12 healthy volunteers. Each subject received a single 10 mg dose of atorvastatin on two separate occasions, separated by 2 weeks. Erythromycin (500 mg qid) was given from 7 days before through 4 days after the second atorvastatin dose. Atorvastatin concentrations were determined by an enzyme inhibition assay, which measured both atorvastatin and active metabolites. When erythromycin was coadministered with atorvastatin, mean Cmax and AUC(0‐∞) increased by 37.7% and 32.5%, respectively. Mean terminal half‐life was similar following each atorvastatin dose. Possible mechanisms for this interaction include erythromycin inhibition of first‐pass conversion of atorvastatin to inactive metabolites and erythromycin inhibition of P‐glycoprotein‐mediated intestinal or biliary secretion.

Renal Dysfunction Does Not Alter the Pharmacokinetics or LDL‐Cholesterol Reduction of Atorvastatin

The objective of this study was to determine the effects of renal dysfunction on the steady‐state pharmacokinetics and pharmacodynamics of atorvastatin, a 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitor. Nineteen subjects with calculated creatinine clearances ranging from 13 mL/min to 143 mL/min were administered 10 mg atorvastatin daily for 2 weeks. Pharmacokinetic parameters and lipid responses were analyzed by regression on calculated creatinine clearance. Correlations between steady‐state atorvastatin pharmacokinetic or pharmacodynamic parameters and creatinine clearance were weak and, in general, did not achieve statistical significance. Although the elimination rate constant, λz (0.579), was significantly correlated with creatinine clearance, neither maximum plasma concentration (Cmax, −0.361) nor oral clearance (Cl/F, 0.306) were; thus, steady‐state exposure is not altered. Renal impairment has no significant effect on pharmacodynamics and pharmacokinetics of atorvastatin.

Pharmacodynamics and Pharmacokinetic-Pharmacodynamic Relationships of Atorvastatin, an HMG-CoA Reductase Inhibitor

The objective of this study is to determine the relationships between plasma atorvastatin concentrations, LDL (low‐density lipoprotein) cholesterol reduction, and atorvastatin dose; the earliest time at which lipid levels change when atorvastatin treatment is initiated or discontinued; and alterations in LDL particle composition. Twenty‐four subjects with elevated LDL‐cholesterol were treated with escalating daily doses of 5, 20, and 80 mg atorvastatin for 6 weeks each. Serial plasma lipid and lipoprotein analyses were performed during the initiation and discontinuation of atorvastatin therapy, as well as at steady state. LDL‐apolipoprotein B and LDL‐cholesterol were measured directly after ultracentrifugation, and LDL‐cholesterol also was estimated by the method of Friedewald. Steady‐state atorvastatin pharmacokinetic parameters were estimated on the last day of each dosing period. LDL‐cholesterol (Friedewald) reductions of 34%, 43%, and 57% were produced by atorvastatin doses of 5, 20, and 80 mg, respectively. The mean dose‐response relationship was log linear, and almost all individual dose‐response curves paralleled the mean curve. LDL‐apolipoprotein B reductions were slightly less than those of LDL‐cholesterol. Atorvastatin area under the curve (AUC(0.24)) values increased proportionally with dose, while values of Cmax (maximum concentration) increased more than proportionally, and Cmin (minimum concentration) increased less than proportionally. Following initiation of dosing, statistically significant decreases in total cholesterol, LDL‐cholesterol (beta quant), and LDL‐apolipoprotein B were observed within 24 hours and in LDL‐C (Friedewald) within 72 hours. Following discontinuation of drug dosing, statistically significant increases were observed in total cholesterol and LDL‐cholesterol (Friedewald) within 48 hours and in LDL‐cholesterol (beta quant) and LDL‐apolipoprotein B within 72 hours. At each dose, an individuals LDL‐cholesterol response was not correlated with AUC(0–24). In conclusion, atorvastatin produces marked LDL‐cholesterol reductions, the mean dose‐response relationship is log linear, almost all individual dose‐response curves parallel the mean dose‐response curve, onset and cessation of action are rapid, the estimated and measured LDL‐cholesterol are the same, LDL‐cholesterol and LDL‐Apo B reductions are similar, and plasma concentrations are not correlated with LDL‐cholesterol reduction at a given dose.

Impact of population pharmacokinetic-pharmacodynamic analyses on the drug development process: experience at Parke-Davis.

BackgroundContinued scepticism about the benefits of population pharmacokinetics and/or population pharmacodynamics, here referred to collectively as the population approach, hampers its widespread application in drug development. At the same time the sources of this scepticism have not been clearly defined. In an attempt to capture and clearly define these concerns and to help communicate the value of the population approach in drug development at Parke-Davis we conducted a survey of customers within the company. The results of this survey are presented here.MethodsAll drug development programmes conducted over the past 10 years that included a population approach in data analysis and interpretation were identified. A brief description of the population analysis was prepared together with a brief description of how the resulting information was used in each drug development programme. These synopses were forwarded to relevant members of each drug development team together with a survey designed to solicit opinions as to the relevance and impact of these analyses.ResultsThe most frequent use of information derived from population-based analysis was in labelling. In all cases of drugs making to New Drug Application (NDA) submission the analyses resulted in information that was included in approved or proposed labelling. In almost half of the cases summarised here (5 of 12), population-based analysis was perceived to have resulted in information that influenced the direction of individual development programmes. In many of these cases the information was serendipitous. It is also noted that most of these analyses were not the result of clearly defined objectives and prospective analysis plans.ConclusionsUse of the population approach, even when applied retrospectively, may have value in complementing or supporting interpretation of other data collected during the course of a trial. Atypical systemic exposure is quickly and easily assessed for correlation with adverse events or exceptional efficacy in retrospective or ad hoc evaluation. Although we know of no direct evidence, it is possible that such use of population pharmacokinetic data has facilitated NDA review and approval by providing insight into the role of atypical systemic drug exposure in otherwise spurious events.

Determination of quinapril and quinaprilat by high-performance liquid chromatography with radiochemical detection, coupled to liquid scintillation counting spectrometry

Quinapril and quinaprilat concentrations were determined in perfusate, urine, and perfusate ultrafiltrate using a specific and sensitive reversed-phase high-performance liquid chromatographic procedure with radiochemical detection, coupled to liquid scintillation counting spectrometry. Quinapril and quinaprilat were measured in perfusate and urine after pretreatment with acetonitrile and subsequent centrifugation. Perfusate ultrafiltrate was used as collected. Two quinapril diketopiperazine metabolites, PD 109488 and PD 113413, were separated chromatographically from quinapril, quinaprilat, and from each other. Assay performance for quinapril and quinaprilat was assessed by examining precision and accuracy of the assay over four days. Using a 100-microliters sample volume, the limit of quantitation for both 3H-quinapril and 3H-quinaprilat (sp. act. approximately 2.0 muCi/micrograms) was 1 ng/ml.

Atorvastatin does not Produce a Clinically Significant Effect on the Pharmacokinetics of Terfenadine

The effect of atorvastatin, a CYP3A4 substrate, on the pharmacokinetics of terfenadine and its carboxylic acid metabolite, fexofenadine, were evaluated. Single 120‐mg doses of terfenadine were given 2 weeks apart to healthy volunteers with 80‐mg daily doses of atorvastatin administered from 7 days before through 2 days after the second terfenadine dose. Concentrations of terfenadine and fexofenadine were measured for 72 hours after each terfenadine dose. Administration of terfenadine alone or in combination with atorvastatin produced no alterations in the QTc interval. For terfenadine, atorvastatin coadministration produced an 8% decrease in maximum concentration (Cmax), a 35% increase in area under the concentration‐time curve extrapolated to infinity (AUC0‐∞), and a 2% decrease in elimination half‐life (t1/2). For fexofenadine, atorvastatin coadministration produced a 16% decrease in Cmax, a 2% decrease in AUC0‐∞, and a 51% increase in t1/2. None of these changes achieved statistical significance. Coadministration of atorvastatin with terfenadine does not result in a clinically significant drug interaction. Because 80 mg is the highest atorvastatin dose used clinically, drug interactions mediated by CYP3A4 inhibition are unlikely in clinical practice.

Pharmacokinetics of Quinapril and its Active Metabolite Quinaprilat During Continuous Ambulatory Peritoneal Dialysis

The pharmacokinetics of quinapril, a novel angiotensin converting enzyme (ACE) inhibitor, and its active metabolite, quinaprilat, were determined following a single 20‐mg oral dose of quinapril in six patients with chronic renal failure maintained on continuous ambulatory peritoneal dialysis (CAPD). Overall, quinapril was well tolerated by these CAPD patients, with mild and transient side effects, not unexpected in this clinical setting, which included pruritus, headache, nausea, and cough. Blood pressure reduction was observed in four of six patients, with onset reliably two to four hours after dosing and duration up to 48 hours, associated with quinaprilat concentrations in plasma above 90 ng/mL for at least 33 hours postdose. Two patients experienced significant hypotension, systolic blood pressure below 90 mm Hg, which responded promptly to oral fluid administration and/or reduction in dialysate tonicity. The pharmacokinetic profile of quinapril in these CAPD patients was not significantly different from that previously observed in healthy subjects with normal renal function and in patients with moderate to severe renal dysfunction not yet requiring dialysis (RDND). The apparent elimination half‐life of quinapril was approximately one hour, with negligible dialysate excretion. The pharmacokinetic profile of quinaprilat in these CAPD patients was similar to that previously observed in patients with RDND. The elimination half‐life of quinaprilat was markedly prolonged when compared to that in healthy subjects and averaged 20 hours, with only a small amount of quinaprilat excreted in dialysate (mean = 2.6% of total dose). In summary, renal failure prolongs both the half‐life as well as the antihypertensive effect of quinaprilat, and CAPD has little or no effect on the disposition of quinaprilat.

Tubular transport mechanisms of quinapril and quinaprilat in the isolated perfused rat kidney: Effect of organic anions and cations

The clearance mechanisms of quinapril and quinaprilat were probed using an isolated perfused rat kidney model. Sixty-four experiments were performed with drug in the absence and presence of classic inhibitors of the organic acid (i.e., probenecid and p-aminohippurate) and organic base (i.e., tetraethylammonium and quinine) transport systems of the proximal tubule. Initial perfusate concentrations of quinapril and quinaprilat were approximately 2.36 μM (or 1000 ng/ml), and transport inhibitors were coperfused at 100–10,000 times the drugs initial μM concentrations. Quinapril and quinaprilat concentrations were determined in perfusate, urine, and perfusate ultrafiltrate using a reversed-phase HPLC procedure with radiochemical detection, coupled to liquid scintillation spectrometry. Perfusate protein binding was determined using an ultrafiltration method at 37°C. Overall, the clearance ratios of quinapril (total renal clearance divided byfu·GFR) and quinaprilat (urinary clearance divided byfu·GFR) were significantly reduced, and in a dose-dependent manner, by the coperfusion of organic acids but not organic bases. The data demonstrate that the organic anionic secretory system is the primary mechanism by which quinapril and quinaprilat are transported into and across renal proximal cells.

The Pharmacokinetics of Quinapril and Its Active Metabolite, Quinaprilat, in Patients with Various Degrees of Renal Function

Single‐ and multiple‐dose pharmacokinetics of quinapril and its active metabolite, quinaprilat, were determined after oral administration of 20 mg quinapril HCl on day 1 and days 4 through 10 in 17 normotensive subjects with various degrees of renal function. Blood and urine samples were collected over 72‐ and 24‐hour periods, respectively, after the first single dose and last multiple dose for measurement of quinapril and quinaprilat concentrations. The renal clearance of quinapril and quinaprilat decreased with increasing renal insufficiency but did not result in significant changes in quinapril pharmacokinetics in patients with renal impairment. In contrast, quinaprilat maximum plasma concentration, trough and peak steady‐state plasma concentrations, area under the plasma concentration‐time curve, and half‐life increased significantly with increasing renal insufficiency. The disposition of quinapril and quinaprilat was unchanged from single to multiple doses. Small changes in the pharmacokinetic disposition of quinapril, together with a decreased rate of quinaprilat elimination, resulted in increased quinaprilat plasma concentrations following administration of both single and multiple quinapril doses to normotensive patients with renal impairment. Thus, quinapril dosage adjustment may be required in some patients with renal impairment.

Pharmacokinetics of quinapril and its active metabolite, quinaprilat, in patients on chronic hemodialysis

The pharmacokinetics of quinapril and its active metabolite, quinaprilat, were evaluated in 12 patients with end‐stage renal disease (ESRD) on chronic hemodialysis. Each subject received a single 20‐mg oral dose of quinapril 4 hours before a 4‐hour hemodialysis treatment. Serial dialysate and blood samples were obtained over 4 and 96 hours, respectively. Samples were analyzed for quinapril and quinaprilat concentrations by gas chromatography. Mean tmax and Cmax values for quinapril were 1.2 hours and 129 ng/mL, respectively. Only one patient had detectable quinapril dialysate concentrations which accounted for 2.8% of the quinapril dose. Mean apparent plasma clearance for quinapril was 1275 mL/min with a mean half‐life of 1.7 hours. Quinapril was extensively de‐esterified to its diacid metabolite, quinaprilat. Mean tmax and Cmax for quinaprilat were 4.5 hours and 671 ng/mL, respectively. Mean apparent plasma clearance for quinaprilat was 24.0 mL/min with a mean half‐life of 17.5 hours. As with quinapril, quinaprilat was not readily dialyzable. Only 5.4% of the administered quinapril dose was recovered as quinaprilat during a single hemodialysis treatment. In view of these results, supplemental quinapril doses need not be routinely given to patients following hemodialysis. Overall, quinapril and quinaprilat pharmacokinetics in patients with ESRD on chronic hemodialysis were not markedly different from those previously observed in patients with moderate to severe renal dysfunction (CLcr < 29 mL/min) not yet requiring hemodialysis (RDND).