Pharmacokinetic–pharmacodynamic model for perindoprilat regional haemodynamic effects in healthy volunteers and in congestive heart failure patients

Abstract

Aims We compared the relationships between the plasma concentrations (C) of perindoprilat, active metabolite of the angiotensin I-converting enzyme inhibitor (ACEI) perindopril, and the effects (E) induced on plasma converting enzyme activity (PCEA) and brachial vascular resistance (BVR) in healthy volunteers (HV) and in congestive heart failure (CHF) patients after single oral doses of perindopril. Methods Six HV received three doses of perindopril (4, 8, 16 mg) in a placebocontrolled, randomized, double-blind, crossover study whereas 10 CHF patients received one dose (4 mg) in an open study. Each variable was determined before and 6±12 times after drug intake. E (% variations from baseline) were individually related to C (ng ml x1 ) by the Hill model E=E max .C c /(CE 50 c +C c ). When data showed a hysteresis loop, an effect compartment was used. Results (meansts.d.) In HV, relationships between C and E were direct whereas in CHF patients, they showed hysteresis loops with optimal k e0 values of 0.13t0.16 and 0.13t0.07 h x1 for PCEA and BVR, respectively. For PCEA, with E max set to x100%, CE 50 =1.87t0.60 and 1.36t1.33 ng ml x1 (P=0.34) and c =0.90t0.13 and 1.11t0.47 (P=0.23) in HV and CHF patients, respectively. For BVR, E max = x41t14% and x60t7% (P=0.02), CE 50 =4.95t2.62 and 1.38t0.85 ng ml x1 (P=0.02), and c =2.25t1.54 and 3.06t1.37 (P=0.32) in HV and CHF patients, respectively. Conclusions Whereas concentration-effect relationships were similar in HV and CHF patients for PCEA blockade, they strongly differed for regional haemodynamics. This result probably expresses the different involvements, in HV and CHF patients, of angiotensinergic and nonangiotensinergic mechanisms in the haemodynamic effects of ACEIs.

The influence of heart failure on the pharmacokinetics of cardiovascular and non‐cardiovascular drugs: a critical appraisal of the evidence

“…However, analysis of the active metabolite perindoprilat yielded different results, with a significant increase in peak concentrations (+220%), a similar time to reach peak concentrations and area under the curve, and a significantly shorter elimination half‐life (−92%) in HF patients. It is not possible to establish whether changes in liver and/or renal function might have influenced the results as the relevant information was not provided in this study . By contrast, no significant alterations in the pharmacokinetics of fosinopril and irbesartan were observed in HF .…”

“…Notably, lisinopril is excreted unchanged almost entirely in the urine (Table S1). Patients with HF treated with oral perindopril had similar peak concentrations, a significantly longer time to reach peak concentrations (+137%) and elimination half‐life (+360%), and a significantly greater area under the curve (+300%) when compared to controls . However, analysis of the active metabolite perindoprilat yielded different results, with a significant increase in peak concentrations (+220%), a similar time to reach peak concentrations and area under the curve, and a significantly shorter elimination half‐life (−92%) in HF patients.…”

“…A total of 59 studies (49 on cardiovascular drugs) investigating 36 drugs (31 cardiovascular) were identified (Tables ). Twelve studies were published in the period 1970–1979 , 20 in the period 1980–1989 , 12 in the period 1990–1999 , 10 in the period 2000–2009 , and five in the period 2010–2018 .…”

“…The contrasting results reported in studies investigating digoxin [37,49,69,81,91,92], bumetanide [51,53], furosemide [38,52,53], lidocaine [42,43,60], mexiletine [61,86] and procainamide [44,[62][63][64]75] might be, at least partly, due to differences in study design and/or participant clinical and demographic characteristics. The available knowledge regarding the pharmacokinetics in HF of other drugs, such as enoximone [50], levosimendan [73], hydroflumethiazide [39], metolazone [40], carvedilol [82], metoprolol [83], nifedipine [54], bosentan [93], hydralazine [55], nicorandil [84], cibenzoline [58], disopyramide [59], ibutilide [85], enalapril [66], fosinopril [77], irbesartan [88], lisinopril [67], perindopril [87], conivaptan [89], tolvaptan [94], dabigatran [95] and darbopoetin [90] is based on results from single studies. However, the data on enoximone, reduced clearance and increased half-life in HF, ...…”

“…Similarly, the study investigating metolazone was conducted in three HF patients and three controls, the population pharmacokinetic study of metoprolol included only five patients with HF, and the study on enalapril did not report statistical analyses [40,66,83]. In the studies investigating hydroflumethiazide, carvedilol, lisinopril and perindopril, there was a marked age difference, not accounted for in statistical analysis, between HF patients and controls [39,67,82,87]. Furthermore, a significant number of these studies did not provide information regarding the NYHA functional class [40,54,59,67,82,89], age [40,50,54,83,84,89,90,93,95], sex [50,54,59,67,83,89,[93][94][95] or presence of significant renal or hepatic impairment [39,40,50,54,84,87,90,95].…”