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The major purpose of this article is to emphasize the need for pharmaceutical scientists to have a better understanding of patent fundamentals. This need is illustrated by analyses of key scientific and legal issues that arose during recent patent infringement cases involving Prozac, Prilosec, and Buspar. Economic incentives for drug discovery and development clash with societal needs for low-cost pharmaceuticals in the United States and all over the world. The Hatch-Waxman Act of 1984 was enacted to promote public health by balancing the interests of brand name and generic companies. Patent protection, which provides a monopoly for a limited time, is aimed to provide such incentives. Creation of patents requires the interaction between scientists and lawyers, an endeavor made difficult by the differing intellectual spheres of their respective disciplines. Therefore, in the first place, a thorough understanding of patent fundamentals among pharmaceutical scientists will help them work more efficiently with patent attorneys. Second, it will enable them to appreciate the strengths and weaknesses of individual patents, which is critical in developing strategies amidst the ongoing patent tug-of-war between brand-name and generic companies.

This chapter will introduce the recently passed Biologics Price Competition and Innovation Act of 2009 (BPCI Act) with special emphasis on the intellectual property (IP) provisions of the law, especially as they relate to patents and trade secrets.It begins with a brief legislative history to provide the reader with an overview of the scientific, legal, economic, and political debate prior to the passage of the BPCI Act. It is followed by a limited presentation of approval guidelines for biosimilarity to enable the reader to obtain a better understanding of the scientific challenges associated with manufacturing biosimilars. Next, key intellectual property provisions under the BPCI Act for innovator and generic manufacturers are presented.This is followed by certain legal issues that have been raised, such as challenges to the U.S. Food and Drug Administration's (FDA's) use of innovator data and postapproval applicability of safe harbor provisions.This chapter concludes with a future perspective that draws the attention of the reader to certain widely debated intellectual property and regulatory issues that will soon be or can be expected to be decided by the FDA and the Supreme Court. These decisions will likely have a major impact on the intellectual property landscape and dialogue for biosimilars. Keywords: biosimilars; Biologics Price Competition and Innovation Act of 2009 (BPCI Act); intellectual property (IP); generic biological product; U.S. Food and Drug Administration (FDA)

Purpose. The purpose of this investigation was to examine the effect of aging on the blood-brain barrier (BBB) transport of tryptophan.

Very little information is available on the permeability of the blood-brain barrier (BBB) to small polar drugs in chronic hypertension. The blood and cerebrospinal fluid (CSF) pharmacokinetics of libenzapril (LZP), a potent angiotensin converting enzyme inhibitor, were investigated in hypertensive (SH) and normotensive (SD) rats. Following intravenous bolus administration of this hydrophilic drug, the terminal rate constant for elimination (beta), steady-state volume of distribution (Vdss), and systemic clearance (CL) were similar in these two animal groups. Other pharmacokinetic parameters (Cpo, alpha, k12, and k21) were significantly (P less than 0.05) greater in the hypertensive group, except for the volume of the central compartment (Vc) and ratio of Vc to Vdss, which were smaller in SH rats. The ratio of area under the concentration-time curve (AUC) in CSF to blood was about twofold higher in SH rats compared to normotensive rats, showing increased BBB permeability in hypertensive rats. An acute brain uptake study was also performed in SH, SD, and WK rats by intracarotid administration of 14C-LZP along with 3H2O as a reference marker. Both LZP and water transport was found to be significantly higher (about two- to five-fold) in six of the seven different brain regions in SH rats as compared to the normotensive (SD and WK) controls. Because of this simultaneous increase in concentrations of both the drug and the reference marker, BUI values were not affected. Regional brain concentrations in SH rats were also linearly correlated with the mean arterial pressure (MAP) values, providing further evidence of the systemic pressure related increase in BBB permeability.

The Dietary Supplement Health and Education Act (DSHEA) was enacted in October 1994 to promote the health of Americans by ensuring easier access to safe dietary supplements. Many supplements such as vitamins, minerals, herbs and amino acids have been reported to be helpful in chronic conditions (i.e., heart disease, cancer and osteoporosis). Under DSHEA, dietary supplements can be marketed without prior FDA approval; the burden is on this agency to show that a marketed dietary supplement is unsafe. However, DSHEA retained the FDA's authority to issue regulations that require the manufacture of dietary supplements be in compliance with current good manufacturing practice (cGMP) standards, which are needed to ensure their quality. Several quality-related concerns of marketed dietary supplements that came to light since the passage of DSHEA prompted the FDA in 2003 to propose rules for cGMP for the manufacture, packaging and holding (storage) of dietary supplements. This review will present the highlights of these proposed rules, focusing on the legislative history of DSHEA, rationale for proposing cGMPs along with a general discussion of the specific requirements. Given the voluminous nature of the specific details, the reader is directed to the pertinent FDA publications for details. In this analysis, selected scientific and legal issues are also discussed to promote a better understanding and implications of these rules.

Hepatic metabolism of salicylic acid was studied using a single-pass liver perfusion technique. Livers obtained from male, Sprague-Dawley rats (200-300 g) were perfused with Krebs-Henseleit bicarbonate buffer containing the drug (50-100 micrograms/mL) and glycine (0.5 or 5 mM) or glucose (5.5 mM) or bovine serum albumin (0.33%). Effluent samples over a 30-50 min interval were analyzed for salicylic acid and its metabolites (gentisic acid, salicyluric acid, and salicyl acyl and salicyl phenolic glucuronides). Effluent concentrations of salicylic acid did not differ from those in the perfusate, indicating that the liver is not a site for the metabolism of this drug. Hepatic uptake studies are needed to confirm this finding.

In the present study the acute effect of intravenous aluminum chloride (1 mg/kg) on choline acetyltransferase (ChAT) and acetyl-cholinesterase (AChE) activities of rats was investigated. Aluminum was found to cross the blood-brain barrier (BBB) as indicated by the detection of aluminum in the cerebrospinal fluid (CSF) 30 min after femoral vein injection. Two hours following aluminum injection, ChAT activity in the basal forebrain and hippocampus was significantly reduced by 30% and 22%, respectively, whereas no change was observed in the caudate nuclei. On the other hand, AChE activity was significantly increased by 45% in the caudate nuclei, whereas little change was observed in other brain areas. This report demonstrates that rapid transport of Al across the BBB, and the acute nature of Al neurotoxicity in rats.

Male Fischer rats received 0.1 mg/kg (bolus) of elemental aluminum as the sulfate salt via the portal (n = 4) or systemic (n = 4) route of administration. Blood and bile were serially sampled over an 8-h period, postadministration. Aluminum was determined by flameless atomic absorption spectrophotometry. Blood aluminum concentrations declined in a monoexponential fashion, with half-lives of 0.7 h (portal) and 1.08 h (systemic) (p less than 0.05). The corresponding systemic clearances were 48.9 +/- 10.6 and 35.1 +/- 3.64 mL/(h.kg) (p less than 0.05). The systemic availability following portal administration was 0.66, indicating a significant "first-pass" effect. Biliary aluminum recovery (% dose) was negligible following both routes [0.83 +/- 0.062% (portal) versus 1.3 +/- 0.22% (systemic), p less than 0.05]. Bile flow decreased approximately 40% (p less than 0.05) immediately upon injection of aluminum via the portal route only; flow remained suppressed throughout the study. This decrease in bile flow was most likely responsible for the lower biliary recovery with this route. In contrast, liver recovery of aluminum at 8-h postadministration was higher with the portal route (65.4 +/- 4.1 versus 39.4 +/- 2.52%). These results show that reported values for oral "bioavailability" of aluminum, often calculated by the standard AUC ratio method, underestimate the true extent of absorption. One mechanism of aluminum-related jaundice observed clinically may be due to cholestasis.

Previous iv studies from our laboratories have shown that the disappearance half-life of blood aluminum increased with dose. Experiments were initiated to determine if saturation of biliary and/or urinary excretion could be responsible for this dose-dependent behavior. Biliary aluminum excretion (0-12 h) accounted for less than 1% of the injected amount at 0.1- and 1.0-mg/kg doses. During the same interval, urinary excretion accounted for 16.7 +/- 2.66 and 8.85 +/- 2.2% of administered dose at the low and high doses, respectively (p less than 0.05); corresponding long term (0 to 13 or 22 days) urinary recoveries were 37.6 +/- 3.67 and 28.4 +/- 1.88% of the injected dose (p less than 0.05), with most (66-70%) of the excretion occurring in the first 24 h. This is consistent with many previous reports showing that urinary excretion is one major elimination pathway for aluminum. Both biliary and urinary clearances decreased with increasing blood aluminum concentration; the biliary and urinary clearance values at low concentrations (500-900 ng/mL) were approximately four- and threefold higher than the corresponding values at higher concentrations (10,000-12,000 ng/mL), respectively. It appears that this apparent saturability of biliary clearance may be due to concentration-dependent of transfer from blood to liver, rather than from liver to bile. In vitro ultrafiltration studies support the hypothesis that decreases in urinary clearance were due to decreased filterability of aluminum at the glomerulus as its blood concentration was increased.(ABSTRACT TRUNCATED AT 250 WORDS)

Aspirin (acetylsalicyclic acid) was administered to rats intravenously, orally, and intraintestinally at different doses or in different dosage forms. The distribution and elimination kinetics of aspirin in rats following intravenous administration were best described by a two-compartmental open system and were dose independent up to 15 mg/kg. The terminal elimination half-life following intravenous dosing (10 mg/kg) was 3.36 +/- 0.85 min (n = 15) with the clearance being 8.40 +/- 1.24 L/(kg.hr). Intravenous distribution and elimination kinetics of aspirin in rats were not influenced by an orally administered buffered solution with a buffer capacity of 0.933 mEq ANC (acid neutralizing capacity) per kg of body weight. However, this orally buffered solution did change the gastrointestinal absorption kinetics of aspirin in rats. The absolute bioavailable dose of aspirin was 56.6 +/- 10.4% (n = 6) following its administration in an unbuffered solution while it was only 31.8 +/- 8.0% (n = 6) following administration in the buffered solution. The corresponding values of the absolute bioavailable doses were 43.4 +/- 3.7% and 25.5 +/- 1.8% following intraintestinal administration. The lower systemic availability of aspirin in the presence of buffer is attributed to a greater fraction of the administered dose becoming available for absorption from the intestine where the extraction efficiency is higher than that in the stomach.

We examined theophylline pharmacokinetics for changes caused by the addition of erythromycin in patients with chronic bronchitis and obstructive pulmonary disease. Twelve hospitalized patients were randomized in a crossover fashion to receive aminophylline and either erythromycin or placebo. After the eighth dose, plasma was analyzed for theophylline, using the enzyme-mediated immunoassay technique. A 6-h urine collection was analyzed for theophylline metabolites, using high-pressure liquid chromatography. Erythromycin significantly decreased mean theophylline clearance by 22% from 4.9 L/min to 3.87 L/min (p less than 0.05). Mean peak theophylline levels increased 28% from 11.9 micrograms/ml to 15.3 micrograms/ml (p = 0.05). No change in urine theophylline metabolites was found. Patients with chronic bronchitis and obstructive pulmonary disease who begin erythromycin while receiving a preexisting therapeutic theophylline regimen experience a significant elevation of theophylline concentration, which predisposes to theophylline toxicity. For those patients with theophylline levels at the higher end of the therapeutic range (15 to 20 micrograms/ml), we recommend an initial 25% reduction in theophylline dosage when erythromycin is added. Serum theophylline levels should be monitored for further refinement of dosage.

An HPLC method for the determination of salicylic acid (SA), gentisic acid (GA), salicyluric acid (SU), and salicyl acyl glucuronide (SAG) in rat urine was developed. The method consisted of extracting SA, GA, and SU from acidified urine into 50:50 mixture of ethyl acetate and butyl chloride. Salicyl acyl glucuronide was extracted from neutral urine after conversion to salicyl hydroxamic acid with hydroxylamine. Salicyl phenolic glucuronide was estimated indirectly as the difference between total salicylate and sum of the four constituents mentioned above. Chromatographic separation was done on a C18 column with U.V. detection at 310 nm using a mobile phase consisting of 5–10% acetonitrile in 3% glacial acetic acid. The extraction recovery of these compounds from spiked urine ranged from 90–108%. The detection limits were 10 μg/ml for GA, SU and SA, and 2.5 μg/ml for SHA. The method was applied to the study of salicylic acid metabolism in the rat.

A high pressure liquid chromatographic assay for promethazine in plasma using electrochemical detection is described. The method was found to be quite reliable and efficient when applied to a bioavailability study involing about 1,000 plasma samples. Using 1 ml aliquots, the lowest detectable concentration was found to be 1 ng/ml. The analysis time averaged about 15 min. per sample. Preliminary results show that systemic availability is better following intramuscular administration of promethazine as compared to the rectal and oral routes.

Male, New Zealand white rabbits (3.5–4.3 kg) received a single 2-mg/kg dose of gold sodium thiomalate (Myochrysine) via intramuscular (N = 4) and intravenous (N = 3) routes. Blood samples were drawn from the marginal ear vein for a period of 5–10 days. The concentration of gold in whole blood was determined using graphite furnace atomic absorption spectrophotometry. The blood concentration–time profiles obtained following both routes of administration were best described by a two-compartment open model with first-order absorption for the intramuscular route. Gold was absorbed rapidly with a mean (harmonic) absorption half-life of 9.0 min, with a peak concentration of 6.0 ± 1.0 µg/ml (N = 4). Blood concentrations declined in a biphasic manner; the mean α half-lives were 0.738 and 1.78 hr for the iv and im routes, respectively. The corresponding terminal (β) half-lives were 54.1 and 63.0 hr. The estimated volume of the central compartment (70 to 93 ml/kg) agreed closely with the rabbit blood volume. The mean ( ±SD) extent of the dose absorbed following intramuscular injection was 68.9 ± 12.4%.

The metabolites of probenecid excreted in the bile of rats with and without ligation of the renal pedicles were investigated using a new GLC assay procedure. Within 8 hr after administration, 63.8% of a 40-mg/kg iv dose of probenecid was accounted for in the bile of normal, anesthetized rats. The metabolites found (as percent of dose) include probenecid (10.0%), probenecid glucuronide (15.7%), glucuronide of the N2-hydroxypropyl derivative (20.3%), glucuronide of the N-3-hydroxypropyl derivative (14.2%), and the unconjugated N-2-carboxyethyl derivative (3.6%). Ligation of the renal pedicles increased the excretion of each metabolite, raising the total recovery to 86.6%. These oxidized metabolites, but not probenecid or its glucuronide, were excreted in urine in unconjugated form (3–5% each). The unconjugated mono-N-depropylated metabolite accounted for 11.2% of the dose in the urine of normal, unanesthetized rats but was not found in the bile of the anesthetized animals.

Four subjects ingested 500, 1000 and 2000 mg of ascorbic acid daily for one week according to a three-way crossover design. Following the last dose, serial urine and plasma samples were obtained over a 12-h period. The ascorbic acid content of these samples were determined by an HPLC method employing electrochemical detection. The plasma concentration-time profiles are similar at all 3 doses, with the area under the curve values (mean ± S.D.) being 206.0 ± 50.5, 212.1 ± 40.7, and 231.8 ± 52.6 mg · h/1 for the 500, 1000 and 2000 mg doses. The corresponding percents (mean ± S.D.) of dose recovered in urine are 73.2 ± 25.7, 46.9 ± 21.7 and35.8 ± 12.4. This decrease in recovery is significantly different ( P

Twenty-four healthy normal volunteers were given 40 mEq of three oral formulations of K+ as potassium chloride in a three-way Latin square design. Pharmacokinetic characteristics of potassium disposition were determined using urinary excretion data. Potassium was absorbed almost instantaneously from the 10% (w/v) solution, while a slow first-order absorption could explain the slow release of potassium from Slow-K and the new slow-release tablet. A biphasic elimination of potassium observed during the first 24 hr of urinary excretion suggested the body's adaptive process of changes in rates of elimination of potassium to maintain homeostasis. There was no significant difference (P = 0.25) in total recoveries of potassium in urine during 48 hr of urinary collection among the three formulations (mean ± SE: solution, 35 ± 7.1 mEq; Slow-K, 38.1 ± 7.8 mEq; and new formulations, 33.5 ± 6.8 mEq). An increased excretion of sodium was observed and correlated with increased potassium excretion following oral potassium administration which could not be explained by changes in urine flow rate. The clinical significance of such an increase in natriuresis is yet to be determined.

Re-evaluation of published data on the urinary excretion of probenecid [4-(dipropylamino)sulfonylbenzoic acid, 1] and its metabolites as a function of orally administered dose has revealed that the elimination process is comprised of five parallel pathways. Excretion of the major metabolite, the acyl glucuronide 2 (35-45% of dose), follows Michaelis-Menten kinetics. The three oxidized metabolites, the mono-N-propyl, carboxylic acid, and secondary alcohol derivatives 3, 4, and 5, respectively, (totaling 30% of dose), each adhere to pseudo-first-order kinetics in which the elimination rate constant, as a result of product inhibition, is a function of the administered dose. Four to 13% of the dose is eliminated unchanged in apparent first-order fashion. A mathematical relationship between elimination half-life and dose, under conditions of product inhibition, is derived. Computer simulation of the elimination process confirms the experimental observation that the fraction of dose excreted in the form of each metabolite remains relatively constant over the dose range of 0.5 to 2 g. This study is believed to represent the first application of parallel Michaelis-Menten and dose-dependent pseudo-first-order processes to drug disposition. It demonstrates that the observation of constant proportions of excreted metabolites over a relatively wide range of doses does not provide evidence that the elimination process remains first-order.

A GLC assay was used to study the excretion of probenecid and its metabolites in the urine of human subjects following oral doses of 0.5, 1, and 2 g. From 75 to 88% of the dose was found in the urine. The major metabolite, probenecid acyl glucuronide, accounted for 34–47% of the dose. Approximately equal amounts (10–15%) of the mono- N -propyl, secondary alcohol, and carboxylic acid metabolites were excreted in the unconjugated form with only traces in the conjugated form. The primary alcohol metabolite was not found in measurable amounts. The terminal half-lives for excretion of all metabolites were in the range of 4–6 hr, were independent of dose, and were limited by their rates of formation. A prolonged time course of excretion of the metabolites, particularly at higher doses, suggests that probenecid, being poorly soluble in water, precipitates from solution in the GI tract, forming a depot of drug from which absorption is dissolution rate limited. The urinary excretion of unchanged probenecid, which accounts for 4–13% of the dose, is dependent on both the pH and flow rate of urine.

Aluminum (Al) kinetics after intravenous bolus administration were studied in the rat. The animals received either 0.1 or 1.0 mg/kg (n = 6 at each dose) of elemental Al as the sulfate salt. The Al content of serial blood samples was determined by flameless atomic absorption spectrophotometry. Blood and plasma Al-time profiles after both doses were monoexponential in most cases. Increasing the administered dose increased the elimination half-life (mean +/- SD) from 1.20 +/- 0.25 to 2.41 +/- 0.26 h. A corresponding decrease in systemic clearance was observed (49.6 +/- 11.0 to 18.4 +/- 4.6 mL/kg.h). Both changes were significant (p less than 0.05). Significant differences were also observed in the volume of distribution, the values of which were 78.3 +/- 17.2 and 58.9 +/- 8.5 mL/kg at the low and high doses, respectively. At both doses, blood:plasma ratios ranged from 0.8 to 1.0, indicating considerable uptake/binding of the element by blood cells.

The mechanism of action of the antiulcer agent, sucralfate, involves drug binding to proteins, pepsin, and bile salts. The potential for sucralfate to bind to, and inhibit the oral absorption of, concurrently-administered drugs has been studied for very few agents. Phenytoin bioavailability was studied following a single dose of phenytoin 500 mg po in nine normal subjects during a control period and when given with sucralfate. Area under the serum concentration-time curve was compared at 48 hours (AUC48) and 120 hours (AUC120) using observed and extrapolated data. The phenytoin AUC48 was reduced from [Formula: see text], and the phenytoin AUC120 was reduced from 200.5 ± [Formula: see text], when sucralfate was administered. Because AUC comparisons for drugs with nonlinear elimination kinetics may reflect changes in rate, as well as extent, of absorption, these small changes in AUC may not reflect a change in the fraction of dose absorbed. However, our results suggest that sucralfate does affect phenytoin absorption. Further studies may be useful in determining the precise nature and clinical importance of this interaction.

Serum aluminum concentrations were determined in ten healthy subjects treated with phenytoin 500 mg and with sucralfate and phenytoin in a crossover fashion. Each subject received four 1,000-mg sucralfate tablets between 8 AM and 10 PM one day before the study, and this was repeated during the study day. A total of eight doses of sucralfate was administered over the two-day period. Serum samples were drawn at 0, 2, 4, 8, 12, 24, 32, and 48 hours after administration. The areas under the serum aluminum concentration-time curves before and after sucralfate (mean +/- SD) were 496.0 +/- 80.9 and 770.9 +/- 146.6 hr-ng/mL, respectively. This increase is statistically significant (P less than .01), indicating that serum aluminum levels are elevated even after two days of treatment with sucralfate. The results from this study are not in agreement with the only other report on this subject.

The objective of this study was to provide a basic understanding of the effect of complexation with copper on the pharmacokinetics of salicylic acid (SA). Male Sprague-Dawley rats (250–300 gms) received an I.V. dose of either SA or copper-salicylate complex, (Cu-SA) (10 mg/kg of SA) in a randomized balanced crossover fashion. Based on free copper ion measurements, the amount of intact complex in the vehicle used to prepare the drug solution for injection ranged between 68.4 and 76.6%. Serial blood samples (100 ul) were drawn for 12 hours post administration. Plasma samples were analyzed for SA by reversed phase HPLC on a C-18 column with U.V. detection at 237 nm. The SA concentration-time profiles were similar up to the first 90 minutes for both treatments. For the remainder of the sampling period, SA concentrations were consistently lower where the animals had received Cu-SA. In rats (n=5) injected with Cu-SA, SA declined monoexponentially with an elimination rate constant (mean ± SD) of 0.0108 ± 0.00146 min-1, a plasma clearance of 2.15 ± 0.621 ml/(min kg) and a Vd of 188.2 ± 38.67 ml/kg. In contrast, rats injected with SA showed a biexponential decline of the drug with a 3 of 0.00475 ± 0.00144 min-1, plasma clearance of 1.08 ± 0.153 ml/(min-kg) and Vd(3) of 243.4 ± 44.96 ml/kg. Non-com-partmental analysis of SA concentration-time data following Cu-SA administration gave Vd(SS) and MRT values of 190.5 ± 31.81 ml/kg and 92.29 ± 9.279 min, respectively. The corresponding values after SA administration were 232.9 ± 40.17 ml/kg and 211.7 ± 73.88 min. Differences in the terminal rate constants, volumes of distribution (Vd(β)), clearances and MRT between the two treatments were significant (p

Cefamandole nafate, cephapirin, and cephalothin were administered intravenously in crossover fashion to 12 volunteers, in dosages of 2 g every 6 h for 16 doses. Mean peak levels of cefamandole were approximately 50% higher than those of the other agents. The serum concentration curves appeared to decline bi-exponentially, suggesting that a two-compartment model was most applicable for pharmacokinetic analysis; accordingly, the t ½ of cefamandole was significantly longer when the serum peak was omitted from the analysis (0.86 versus 0.73 h, P < 0.05). The half-lives of cephalothin and cephapirin, 0.34 and 0.36 h, respectively, were probably underestimates reflecting the inclusion of distribution-phase values in the calculation. Repeated dosing had no effect on the peak serum levels, half-life, serum clearance, or apparent volume of distribution with one exception: peak serum levels of cephapirin were significantly lower after the sixteenth than after the first dose. Marked variations within a given subject were noted in the half-life and apparent volume of distribution of cefamandole in several instances. Renal clearances of cefamandole exhibited saturation kinetics similar to those of penicillin G.