Patrick K. Noonan

Incomplete and delayed bioavailability of sublingual nitroglycerin.

Eight healthy male volunteers received 16 doses of sublingual nitroglycerin tablets (0.4 mg). After 8 minutes, each subject rinsed out his mouth to halt the drug absorption process. The mouth rinses were assayed by high-performance liquid chromatography for residual nitroglycerin content. Each subject also received intravenous infusions of nitroglycerin so that the absolute bioavailability could be evaluated. Plasma nitroglycerin concentrations were determined using a specific and sensitive capillary gas chromatographic method capable of quantifying 25 pg/ml of nitroglycerin. The mean bioavailability (+/- standard deviation) of sublingual nitroglycerin, estimated from plasma concentrations, was 36.2 +/- 24.9% (range 2.6 to 113%). The amount of drug not absorbed after 8 minutes, as determined from the analysis of the mouth rinses, varied from 2.7 to 65.8% (mean 31.4 +/- 18.9%) of the administered sublingual dose. Mean nitroglycerin peak concentrations of 1.89 +/- 1.64 ng/ml were obtained at a mean peak time of 5.3 +/- 2.3 minutes. Thus, sublingual absorption is not instantaneous and can be relatively slow, with peak times of as long as 10 minutes. These data indicate that nitroglycerin pharmacokinetic values should not be estimated only from sublingual doses. Additionally, attempts to correlate pharmacodynamic measurements to sublingual doses must take into account the low and variable bioavailability and the potentially long peak times after sublingual nitroglycerin administration to patients.

Dose Dependent Pharmacokinetics of Nitroglycerin After Multiple Intravenous Infusions in Healthy Volunteers

Evaluation of the pharmacokinetics of nitroglycerin has been hindered in the past by the lack of specific and sensitive analytical procedures, and the unavailability of parenteral nitroglycerin and infusion sets which did not adsorb nitroglycerin. The purpose for this present study was to determine the pharmacokinetic parameters of nitroglycerin and the dinitrate metabolites after multiple intravenous infusions of nitroglycerin in healthy volunteers. Six volunteers received variable infusion rates of nitroglycerin. Generally, at 0, 40, 80, and 120 min, the infusion rates were adjusted to 10, 20, 40, and 10 μg/min, respectively. Plasma samples were drawn and analyzed for nitroglycerin and its 1,2-and 1,3-dinitraie metabolites using capillary GC. Steady-state nitroglycerin plasma concentrations attained at 10, 20, 40, and 10μg/min were 0.44±0.31, 1.32±0.71, 4.23±1.50 and 1.04±0.43 ng/ml, respectively. As the infusion rate was increased, the steady-state concentrations increased disproportionately. When the dose was decreased from 40 to 10μg/min, the steady-state nitroglycerin concentrations were always higher than those at the initial low infusion rate. Thus, in the majority of subjects, a hysteretic type of response was present. The hysteresis observed in the dose versus steady-state concentration curve may be explained by either end-product inhibition or saturable binding of nitroglycerin to blood vessels. The clearance values (5.5 to 71 l/min) were very high and far exceed the maximum possible hepatic clearance suggesting that nitroglycerin is metabolized by organs other than liver. Clearance was not directly related to plasma concentrations but was found to decrease to a constant value (approximately 11±6 l/min< as nitroglycerin concentrations initially increased.

Percutaneous absorption of testosterone in the newborn rhesus monkey: comparison to the adult.

Summary: Percutaneous absorption of testosterone was determined in newborn rhesus monkeys, an animal model which is relevant to man. Mean percentage of absorptions of 4 and 40 μg/cm2 in the newborn were, respectively, 22.5 ± 2.2 (SD) and 6.8 ± 2.1. Statistical comparisons (Students t-test) of these results with those obtained with adults show no significant difference (P > 0.05) in skin penetration of testosterone in newborn and adult rhesus monkeys. In the newborn, the efficiency of absorption (percentage) decreased when the topical dose was increased 10-fold. However, the total compound absorbed per cm2 area of skin actually increased from 0.9 to 2.7 μg.With one other newborn rhesus, a topical dose of 40 μg/cm2 was applied to the ventral forearm and the area was occluded for 24 hr. Percutaneous absorption was 14.7%, a value twice that from nonoccluded absorption.Systemic absorption from a topical dose becomes critical in the newborn because the ratio of surface area (cm2) to body weight (kilograms) in the newborn is 3 times that in the adult. Given equal application area of skin per newborn and adult, the systemic absorption in the newborn becomes 3 times that of the adult when based on kilograms body weight. With a different ratio of skin surface to body weight, the therapeutic ratio probably is lower in the newborn than in the adult when the compound is applied topically.Speculation: A high percentage of a steroid compound can be absorbed through the skin of a newborn as well as an adult. The systemic availability of a drug to the newborn following topical application can be 3 times that of the adult, per unit of body weight.

Transdermal bioavailability and first-pass skin metabolism: A preliminary evaluation with nitroglycerin

A model comprising six compartments, a systemic and presystemic compartment for nitroglycerin and each of its two dinitrate metabolites is presented to describe the interrelationships between plasma concentrations of the two metabolites and metabolism in skin after intravenous and transdermal ointment administration of nitroglycerin. Using a perfusion-limited pharmacokinetic model, the equation for the calculation of the fraction (F)of the dose of nitroglycerin systemically available from skin was derived independent of nitroglycerin plasma concentrations. Estimated Fvalues (0.68–0.76) are comparable to values reported in Rhesus monkeys (0.80–0.84). Simulated plasma concentration-time profiles were reasonably fitted to the observed concentrations of nitroglycerin and its two metabolites after transdermal administration. This preliminary model suggests that transdermal bioavailability for a drug metabolized in the skin can be reasonably estimated.

Passive Transdermal Systems Whitepaper Incorporating Current Chemistry, Manufacturing and Controls (CMC) Development Principles

In this whitepaper, the Manufacturing Technical Committee (MTC) of the Product Quality Research Institute has updated the 1997 Transdermal Drug Delivery Systems Scale-Up and Post Approval Change workshop report findings to add important new product development and control principles. Important topics reviewed include ICH harmonization, quality by design, process analytical technologies, product and process validation, improvements to control of critical excipients, and discussion of Food and Drug Administration’s Guidance on Residual Drug in Transdermal and Related Drug Delivery Systems as well as current thinking and trends on in vitro–in vivo correlation considerations for transdermal systems.

Variable glyceryl dinitrate formation as a function of route of nitroglycerin administration

Plasma concentrations of 1,2‐ and 1,3‐glyceryl dinitrates were measured in each of four healthy volunteers who received intravenous infusions (10, 20, and 40 μg/min), topical ointment (20 mg/200 cm2), and oral solution (6.5 mg) doses of nitroglycerin and from two subjects who received sublingual (0.4 mg) nitroglycerin. The ratio of 1,2‐glyceryl dinitrate to 1,3‐glyceryl dinitrate (dinitrate ratio) was determined for each subject after each dose and was found to vary with route of administration. Dinitrate ratios were 7.36, 4.60, 3.86, and 1.99 for intravenous, sublingual, topical, and oral doses, respectively. Nonspecific metabolism of nitroglycerin would result in twice as much of the 1,2‐dinitrate as the 1,3‐dinitrate (i.e., a dinitrate ratio of 2.0, such as that produced after oral administration). A high ratio (e.g., after intravenous administration) indicates that the metabolism was more specific. These results indicate that metabolite formation depends on route of administration, implying different metabolic specificity of enzymes in the gut, liver, skin, sublingual mucosa, and blood vessels.

The Impact of Lag Time on the Estimation of Pharmacokinetic Parameters. I. One-Compartment Open Model

Lag time in pharmacokinetics corresponds to the finite time taken for a drug to appear in systemic circulation following extravascular administration. Lag time is a reflection of the processes associated with the absorption phase such as drug dissolution and/or release from the delivery system and drug migration to the absorbing surface. Failure to specify the lag time can lead to inappropriate or erroneous estimates of pharmacokinetic parameters. This has been demonstrated in the case of a one-compartment open model by the pharmacokinetic analysis of bioequivalence data from a study involving the administration of propoxyphene napsylate to human volunteers. Subsequently, pharmacokinetic and statistical analyses of data obtained from a series of 49 simulations involving a wide range of absorption and elimination rate constants (0.05 to 5.00 and 0.01 to 0.95 hr−1, respectively) showed that lag time has a substantial effect on several primary and secondary pharmacokinetic parameters.

Best Practices for the Development, Scale-up, and Post-approval Change Control of IR and MR Dosage Forms in the Current Quality-by-Design Paradigm

In this whitepaper, the Manufacturing Technical Committee of the Product Quality Research Institute provides information on the common, best practices in use today in the development of high-quality chemistry, manufacturing and controls documentation. Important topics reviewed include International Conference on Harmonization, in vitro–in vivo correlation considerations, quality-by-design approaches, process analytical technologies and current scale-up, and process control and validation practices. It is the hope and intent that this whitepaper will engender expanded dialog on this important subject by the pharmaceutical industry and its regulatory bodies.

PHARMACOKINETICS AND THE VARIABILITY OF PERCUTANEOUS ABSORPTION

AbstractTransdermal delivery systems have gained wide acceptance over the past decade. These systems allow more control over the surface area and, therefore, the doses delivered to a patient compared to conventional ointments and creams; however, as with ointments, the skin and not the delivery system controls the absorption rate for most drugs. The in vivo percutaneous absorption of nitroglycerin, a highly potent cardiovascular drug with good absorption characteristics, has been investigated over the course of 5 years in more than 300 subjects. Various types of delivery systems, utilizing gel and adhesive matrices and “membrane control” were included in these investigations. Each subject received at least two different formulations on 2 different days. The delivery systems were left in place for 24 hr, after which they were removed and subsequently analyzed for residual nitroglycerin content. The apparent dose for each subject was determined. This parameter is defined as the difference between the initia...

High-Performance Liquid Chromatographic (HPLC) Assay Using Fluorescence Detection for the Simultaneous Determination of Gallopamil and Norgallopamil in Human Plasma

Gallopamil is a calcium-channel antagonist with reported activity in experimental animals three to five times higher than that of verapamil. An automated high-performance liquid chromatographic (HPLC) method with fluorescence detection is described for the simultaneous determination of gallopamil and its metabolite norgallopamil in plasma. Gallopamil was well resolved from norgallopamil and other metabolites, allowing simultaneous quantitation of both drugs. The detection limit for both gallopamil and norgallopamil was 0.9 ng/ml. This method has been successfully used for the determination of gallopamil and norgallopamil following the administration of 25-, 37.5-, and 50-mg oral doses of drug.