Peter A. Meredith

Bioequivalence and other unresolved issues in generic drug substitution

BACKGROUND Substitution of generic drugs for brand-name products is highly controversial and often is met with suspicion by health care providers and patients. Historically, the debate has focused on the issue of bioequivalence, and clinical practice has identified a number of drug classes for which generic substitution should be approached with caution. Current bioequivalence requirements are based on a measure of average bioequivalence; however, there are fears that use of this measure may be inappropriate in the case of a drug with a narrow or wide therapeutic range or high intrasubject or intersubject variability. Under these circumstances, measures of individual and population bioequivalence are proposed to be more accurate than measures of average bioequivalence. OBJECTIVE This paper addresses issues of bioequivalence and other concerns with generic drug substitution. METHODS I conducted a MEDLINE search of the English-language literature containing the key terms generic, multisource, quality, and brand and published between 1973 and 2003. The names of branded pharmaceuticals whose patents had recently expired (eg, Ventolin HFA, Adalat, Capoten, Tagamet HB 200, and Valium) also were used to search for articles on generic substitution. Reference lists of relevant articles also were searched. Bioequivalence issues are presented together with more general concerns over generic drug substitution, such as consumer perception of risk, differences in product and packaging appearance, and differences in excipients. RESULTS The literature reviewed act to highlight a number of different drug categories and patient subpopulations for which generic substitution can still prove to be problematic. CONCLUSION I recommend that health care providers continue to exercise caution in the consideration of generic drug substitution under certain circumstances.

Enalapril clinical pharmacokinetics and pharmacokinetic-pharmacodynamic relationships. An overview.

SummaryThe conventional pharmacokinetic profile of the angiotensin converting enzyme (ACE) inhibitor, enalapril, is a lipid-soluble and relatively inactive prodrug with good oral absorption (60 to 70%), a rapid peak plasma concentration (1 hour) and rapid clearance (undetectable by 4 hours) by de-esterification in the liver to a primary active diacid metabolite, enalaprilat.Peak plasma enalaprilat concentrations occur 2 to 4 hours after oral enalapril administration. Elimination thereafter is biphasic, with an initial phase which reflects renal filtration (elimination half-life 2 to 6 hours) and a subsequent prolonged phase (elimination half-life 36 hours), the latter representing equilibration of drug from tissue distribution sites. The prolonged phase does not contribute to drug accumulation on repeated administration but is thought to be of pharmacological significance in mediating drug effects.Renal impairment [particularly creatinine clearance <20 ml/min (<1.2 L/h)] results in significant accumulation of enalaprilat and necessitates dosage reduction. Accumulation is probably the cause of reduced elimination in healthy elderly individuals and in patients with concomitant diabetes, hypertension and heart failure.Conventional pharmacokinetic approaches have recently been extended by more detailed descriptions of the nonlinear binding of enalaprilat to ACE in plasma and tissue sites. As a result of these new approaches, there have been significant improvements in the characterisation of concentration-time profiles for single-dose administration and the translation to steady-state. Such improvements have further importance for the accurate integration of the pharmacokinetic and pharmacodynamic responses to enalapril(at) in a concentration-effect model. This model is able to characterise the concentration-effect relationship in individual recipients of the drug and predict the antihypertensive responses to dosage alterations.Therapeutic use of enalapril has recently expanded to include heart failure. In this condition, responses to enalapril may be mediated by different effector systems in different organs and may occur at different concentration ranges to those observed during treatment of hypertension. However, similar concentration-effect analyses are still relevant. After almost 15 years of clinical use, the therapeutic applicability of enalapril continues to expand and detailed pharmacokinetic description of the agent remains an integral component of this expansion.

Angiotensin II Receptor Antagonists Alone and Combined with Hydrochlorothiazide Potential Benefits Beyond the Antihypertensive Effect

Angiotensin II receptor antagonists (angiotensin receptor blockers; ARBs) and thiazide diuretics have an accepted place in the management of hypertension. Most patients require combination therapy with two or more drugs to adequately control blood pressure to targets recommended by European and international guidelines. ARBs and the thiazide diuretic hydrochlorothiazide have complementary modes of action. Fixed-dose combinations of an ARB and low-dose hydrochlorothiazide provide a convenient and effective treatment option for patients who do not achieve blood pressure targets on monotherapy, without compromising the placebo-like tolerability of ARBs. In Europe, fixed-dose combinations with hydrochlorothiazide currently are available for the ARBs candesartan, eprosartan, irbesartan, losartan, telmisartan, and valsartan. Recently, a number of studies have focused on the use of ARBs in monotherapy and in combination therapy, in conditions including congestive heart failure, post-myocardial infarction management, hypertension with cardiovascular risk factors, and diabetic and non-diabetic nephropathy. Evidence from these studies suggests a beneficial role beyond the antihypertensive effect of these therapies in providing protection against cardiovascular, renovascular, and cerebrovascular events.

Pharmacodynamic modeling of the antihypertensive response to amlodipine

The distinctive pharmacokinetic characteristics of amlodipine, particularly the long half‐life, are presumed to translate directly to a prolonged duration of action, but the concentration‐effect relationship for the antihypertensive response has not been clearly established. In this study of 12 patients with essential hypertension, treatment with 5 mg amlodipine once daily has been evaluated with use of an integrated pharmacokinetic‐pharmacodynamic model to calculate individual patient responsiveness for the decrease in blood pressure per unit change in drug concentration. Amlodipine concentrations were well correlated with the placebo‐corrected reductions in blood pressure in individual patients and responsiveness, for example, for erect systolic blood pressure was − 3.1 ± 0.9 mm Hg/ng/ml. By characterizing the concentration‐effect relationships in individual patients, this study has confirmed that the plasma concentration–time profile is an appropriate index of the effect‐time profile, as reflected by an antihypertensive response that is sustained throughout 24 hours with relatively little trough‐to‐peak variability.

Optimal dosing characteristics of the angiotensin II receptor antagonist telmisartan

An optimal antihypertensive drug produces superior blood pressure-lowering effects at established dosages, with an acceptably low incidence of side effects, and at a dosage interval that is convenient for patients (ideally, once daily). The angiotensin II receptor antagonist, telmisartan, meets these criteria. At doses of > or = 40 mg, this once-daily drug produces a statistically significant reduction in blood pressure. Ambulatory blood pressure monitoring (ABPM) and high trough-peak ratios attest to the smooth, consistent blood pressure-lowering effect of telmisartan at 40- and 80-mg dosages. Telmisartan also demonstrates a statistically superior antihypertensive effect toward the end of the dosing interval compared with amlodipine and losartan, and it has a side-effect profile comparable to that of placebo. In summary, the evidence suggests that telmisartan at dosages of 40 and 80 mg once daily satisfies the 3 criteria of an ideal antihypertensive agent, producing an effective and sustained response with placebo-like tolerability.

Antihypertensive drugs: Individualized analysis and clinical relevance of kinetic-dynamic relationships

Individualized approaches to antihypertensive therapy are being widely advocated. Ideally these should incorporate rational prospective methods for drug and dosage selection but progress has been hampered by the paucity of information about dose- (and plasma concentration-) response relationships. However, in several recent clinical studies, concentration-effect analysis has been used to characterize kinetic-dynamic relationships in individual patients for a range of antihypertensive drugs. This approach provides an integrated mathematical description of drug response which has potential utility for quickly identifying poor or nonresponders and for determining individual dose requirements for optimum longterm blood pressure control.

Differential effects of ACE inhibiting drugs: Evidence for concentration‐, dose‐, and agent‐dependent responses

Clinical Pharmacology and Therapeutics (1993) 53, 622–629; doi:10.1038/clpt.1993.82

ACE inhibition and AT(1) receptor blockers: efficacy and duration in hypertension.

Regardless of the time of day that it is measured—whether it be during the morning, the afternoon, the evening, and night time—there is a parallel, incremental, upward shift in blood pressure in the vast majority of hypertensive patients when compared with normotensive individuals. Intuitively it would therefore seem appropriate that strategies to reduce blood pressure should be effective throughout the 24 hour period in a consistent fashion (fig 1). Figure 1 Intra-arterial blood pressure profiles over a 24 hour period. Epidemiological evidence reveals that the highest number of cardiovascular events occur in the early morning period and this corresponds to the time when there is a surge in blood pressure.1 Blood pressure is not necessarily at its highest at this point, but there is a sharp rise from the inherently low levels during the night time period to those around the time of wakening. It should be appreciated, however, that there are also other events that occur at this time such as changes in platelet aggregability and catecholamines. Importantly, as most patients take their antihypertensive medication in the morning, the surge in blood pressure also corresponds to the period with minimum pharmacological cover—that is, 24 hours post dose with a once a day regimen. Epidemiological evidence also shows that blood pressure variability itself is an independent determinant of target organ damage. Thus, for any given level of average blood pressure, where variability around that mean is greater, the patient is likely to be more susceptible to evidence of hypertension related end organ damage.1 Furthermore, there is evidence to support the contention that drug induced blood pressure variability may also be deleterious. In patients who fail to show the “normal” circadian dip in night time blood pressure there is evidence of increased cardiovascular risk.1 Initially this was demonstrated in …

The Effect of Carbon Monoxide upon Erythrocyte δ-Aminolevulinicacid . Dehydratase Activity

The activity of the delta-aminolevulinicacid dehydratase enzyme in the second reaction of the heme biosynthetic pathway has been determined in human blood in the presence of varying concentrations of carboxyhemoglobin. In vivo and in vitro carbon monoxide exposure causes a consistent, but small, significant diminution of activity. At concentrations of carboxyhemoglobin likely to be found in vivo it is unlikely to significantly influence the use of this enzyme as a measure either of lead exposure or of ethanol consumption.

The pharmacodynamics and pharmacokinetics of the combination of nifedipine and doxazosin

SummaryIn a single-blind study 12 normotensive men took nifedipine 20 mg (Group 1, n=6) or doxazosin 2 mg (Group 2, n=6), followed by the combination. Each subject attended on four 9-h study days for evaluation of the effects of single and multiple doses of the monotherapy and the effects of adding single and multiple doses of the second drug. Measurements of BP, HR, plasma drug concentrations, and apparent liver blood flow were recorded. The combination was generally well tolerated.BP was consistently lower with the combination than with either monotherapy: for example, average erect BP was 108/61 (Group 1) and 112/62 mmHg (Group 2) compared with 122/66 and 116/68 during steady-state monotherapy.The introduction of nifedipine in Group 2 was associated with a significant increase in liver blood flow at 1.5 h: 1560 vs 1050 ml · min−1 during monotherapy with doxazosin.There was no significant kinetic interaction. In particular, the steady-state AUC of doxazosin was unaffected by the addition of nifedipine: 257, 307, 301, and 256 ng · ml−1 · h for the 4 study days (Group 2).