Physicochemical Factors Affecting Drug Performance PDF

# Physicochemical Factors Altering Biological Performance of Drugs ## Particle Size - Particle size is important for drugs of low solubility in water or biological fluids - Examples: stomach fluid, intestinal fluid, etc. - The critical point seems to be if the solubility is less than 0.3...

# Physicochemical Factors Altering Biological Performance of Drugs ## Particle Size - Particle size is important for drugs of low solubility in water or biological fluids - Examples: stomach fluid, intestinal fluid, etc. - The critical point seems to be if the solubility is less than 0.3 percent. - The U.S. FDA regulation on bioavailability lists 0.5 percent as the limit. - With decreasing particle size, surface area increases - This leads to increased area of solid matter exposed to the dissolution media - This increases dissolution rate (becomes more rapid). - However, the actual solubility does not significantly change with particle-size reduction (micronization) in the range used in pharmaceutical manufacture. $$ \frac{dc}{dt} = k_a(C_s - C_t) $$ Where: - **dc/dt** = dissolution rate (amount per unit time) - The Noyes-Whitney equation - **k_a** = constant depending on intensity of agitation, temperature, structure of solid surface and diffusion coefficient - **a** = surface area of undissolved solute - **C_s** = solubility of drug in solvent - **C_t** = concentration of dissolved drug at time t - Examples of drugs for which therapeutic differences have been found depending on particle size: - Amphotericin, aspirin, bishydroxycoumarin (dicumarol), chloramphenicol, digoxin, fluocinolone acetonide, griseofulvin, p-hydroxypropiophenone, meprobamate, nitrofurantoin, phenobarbital, phenothiazine, phenylbutazone, prednisolone, procaine penicillin, reserpine, sodium para-aminosalicylate, spironolactone, sulfadiazine, sulfisoxazole, and tolbutamide. - The decrease in particle size is technically limited. - The smallest particle sizes used are in the range of 1-10 µm. - Particle size reduction is not a universal answer for all drugs of low solubility. - For instance, if the dissolution rate is not the absorption rate-limiting step or in cases where decomposition of the drug would be faster than the time needed for absorption - Example: micronized penicillin G in gastric fluid, then micronization should be avoided. ## Co-Solutes and Complex Formation - Co-solutes are of importance only for drugs of low solubility ### Salting-Out - If an electrolyte is added in solid form to a solution of an organic nonelectrolyte: - The ions of the added electrolyte require water for their hydration - This reduces the amount of water available for the solution of the nonelectrolyte - The nonelectrolyte will be precipitated → salting out. - **Diagram:** - Show a container with water, solid NaCl, and organic nonelectrolyte dissolved in the water. - Organic nonelectrolyte is precipitated to the bottom of the container as the sodium chloride dissolves ### Salting-In - Salting-In occurs when: - The salts of various organic acids - Organic-substituted ammonium salts - Are added to aqueous solutions of nonelectrolytes. - In the first case, the solubilizing effect is associated with the anion - In the second case with the cation. - The added compound adds to the hydrophilicity of the solution. - **Diagram:** - Show a container with water, solid (organic acids or salts of organic NH compounds), and organic nonelectrolyte dissolved in the water. - The organic nonelectrolyte is shown dissolved in the water. - The solid (organic acids or salts of organic NH compounds) dissolve and contribute hydrophilic groups. ### Clathrate Formation - Clathrates are formed if a substance is capable of forming channels, or cages which can take up another substance into the intraspace of the structure. - Clathrate-forming substances are gallic acid, urea, thiourea, amylose, and zeolite. - Clathrates are formed by crystallization of an organic solution of the clathrate-forming vehicle substance with the drug. - **Diagram:** - A container filled with organic solution for clathrate forming material - A filter that passes the organic solution of drug - A container filled with a solution of drug and clathrate forming material. - The clathrate forming material will crystalize or precipitate - The drug is in monomolecular dispersion in the clathrate complex. - If exposed to water, the clathrate-forming vehicle dissolves rapidly and exposes the single molecule of drug to the dissolution media. - Drugs used in clathrates are: vitamin A, sulfathiazole, chloramphenicol, and reserpine. - Clathrates are stable in the dry form. ### Solid-in-Solid Solution Complex - If a drug is dissolved in a melt of mannitol or a mixture of mannitol and other carbohydrates or of succinic acid - And the mixture is solidified or crystallized, a solid-in-solid solution is obtained whereby the drug is in monomolecular dispersion. - **Diagram:** - A container with a solidified melt of a drug in a solidified melt of mannitol or succinic acid - A mill that mills the solid-in-solid solution - A container filled with dissolved drug in water - Other substances which yield solid-in-solid solution complexes are mixtures of creatinine and tartaric acid and organic solutions containing either polyvinylpyrrolidone or polyethylene glycol. - The liquid melt can be used for spray-congealing to obtain beads or the solidified melt may be milled. ## Chemical Variation - Chemical variations are made for two reasons: - To change the structure of the active compound in order to increase pharmacologic response, - To maintain the basic structure but change solubility by formation of either salts, esters, ethers, or complexes. - The last group (salts, esters, ethers, complexes) is of biopharmaceutical importance. ### Salts - In general, the salts of electrolytes have a higher solubility and a more rapid dissolution rate than the free acid or the free base. - The dissolution rate of an acidic drug increases with increasing pH - However, not to the same extent as the solubility increases with increasing pH (salt formation). - The dissolution rate of a salt is relatively independent of the pH of the medium. - **Diagram:** Show a container with solid organic acid and water with pH 1-3 and another container with a solid particle of salt of organic acid, a diffusion layer with pH 5-6, and a gastric membrane. ### Esters - Chloramphenicol and erythromycin are absorbed from the gastrointestinal tract in form of free bases. - However, these are unstable in acidic gastric fluid. - For example, chloramphenicol esters dissolve at higher pH in the small intestine and are subsequently enzymatically hydrolyzed. - Different esters have different rates of hydrolysis. - Chloramphenicol palmitate is more readily hydrolyzed than chloramphenicol stearate. ### Amorphous and Crystalline - Solid particles are either amorphous or crystalline. - In general, the amorphous state is more soluble and has a higher dissolution rate than the crystalline form. - Probably the crystalline form requires a higher amount of energy to free a molecule of drug from it than does the amorphous form. - Examples: amorphous novobiocin and amorphous chloramphenicol esters are biologically active while their crystalline forms are inactive. - Penicillin G should not be used in amorphous form PO because it is more rapidly dissolved and inactivated in stomach fluid than the crystalline form. ### Anhydrous Form, Hydrates, and Solvates - Hydrates are addition-compounds of drug with water, while solvates are addition-compounds of drug and organic solvent. - Their physical properties differ greatly from the anhydrous form in respect to solubility and dissolution rate. - For example, the anhydrous form of ampicillin, upon exposure to water, the vehicle dissolves rapidly releasing the drug in monomolecular state. - **Diagram:** - Show a container with solid co-precipitate of drug and macromolecular carrier, a filter, a container with dissolved drug. - Examples of drugs used in solid-in-solid solutions: - Griseofulvin, chloramphenicol, acetaminophen, aminobenzoic acid, beta-cyclodextrin, and antihistamines in melts of urea, mannitol, succinic acid, etc., and of salicylic acid, sulfathiazole, prednisone, salicylamide, pentaerythritol tetranitrate, and griseofulvin in polyvinylpyrrolidone or polyethylene glycol solutions. ## Manufacturing Factors - Many unit operations used in manufacture of drug products may decrease biological performance. - In the case of tablets, increased compression force increases "hardness" - Mechanical resistance of tablets - This prolongs disintegration and dissolution time. - Increasing amounts of binders in granules and tablets increase "hardness" - Mechanical resistance of tablets - This prolongs disintegration and dissolution time. - Increasing amounts of lubricants decrease hydrophilicity and wetting of tablets, thus prolonging disintegration and dissolution time. - "Hard" granules and high compression speed and high compression force may cause a rise in the temperature of tablets during the moment of compression to 75°C. - At which temperature some drugs may sinter. - A micronized drug may hence form larger aggregates. - Heat used in manufacture of suppositories and ointments may cause some drugs to dissolve in the base. - Upon cooling, the drug may crystallize and form large needles, thus prolonging the time of drug release. ## Dissolution - When a drug substance dissolves in a dissolution medium, a cube root law most often is applicable, if sink conditions apply. - An exponential decay of mass dissolved versus time is applicable, if nonsink conditions apply. - In most cases, however, there will be a lag time due to interfacial effects. - For the drug substance itself, the most important interfacial effect is that of the wetting of the planes of the solid. - For hydrophilic solids, “wetting” is complete in the sense that the contact angle is zero. - For less hydrophilic to hydrophobic substances, the contact angle increases, and if the contact angle is less than π/4, then the wetting is generally complete. - However, this requires time. - For the dissolution under sink conditions, the cube root law with lag time takes the following form: - M is mass not dissolved; - t is time; - t₁ is the lag time; - K is a cube root dissolution constant; - M₀ is the original mass. $$ M^{1/3} = M_0^{1/3} -K.(t-t_1) $$ - Under nonsink dissolution into an adequate dissolution volume (V), it is exponential-asymptotic so that introducing a lag time for wetting would give: $$ C=(M_0/V)•(1-e-q(t-t_1)) $$ - It is noted, however, that the wetting is important in the beginning of the dissolution. - If the area, A, wetted is linear in time, i.e., if: $$ A=f.t $$ - where f is a constant, then the lag time is given by: $$ t_1 = A/f $$ - It can be assumed that sink conditions apply prior to t₁, so that: $$ dm/dt =-k.A.S $$ - Substituting Equation 9.4 in Equation 9.6 gives: $$ dm/dt = -k (ft).S $$ - If the drug dissolves slowly and/or there is an excess present, then A may be assumed to be fairly constant, and equal to A_o, and in this case, Equation 9.7 integrates to: $$ M=M_o-(k.f.S/2).t^2 $$ - Or: $$ C=(M_o-M)/V=(k.f.S/2V).t^2 $$ - where V is liquid volume and S is solubility. At t = A/f, the concentration is: $$ C'=(k.SA/2V.f) $$ - Since the dissolution occurs under sink conditions at the low time points, the profile is one of a parabola at first, which, at the point given in Equation 9.10 (where all the solid is wetted), becomes the straight line: $$ C'=kAS (t-t_1) $$ - If Equation 9.10 is inserted in Equation 9.11, it is found that: $$ t₁ = (A-(1/2V))·(1/f) $$ ## Conclusion - Pharmacotechnical factors, although of different kinds, may alter biological performance of drugs by changing the rate and extent of drug release (liberation) from the dosage form upon administration. - A prerequisite of drug absorption is that the drug be in aqueous (true) solution (except in the relatively rare case of pinocytosis). - The process of bringing a drug into solution at the site of absorption is the liberation or drug relapse process. - Drug release can be determined in vitro by means of a dissolution rate test for peroral and oral dosage forms, or by dialysis or diffusion methods for rectal and topical preparations. ## Drug Products Having Different Release Characteristics - Drug products having different release characteristics will result in different blood level curves in vivo. - If the extent of drug release is identical, there will be identical areas under curves depicting blood level versus time. But the release rates differ, the blood level versus time curves will show different absorption rate constants and different peak heights. - The different absorption rate constants so obtained are artifacts because the actual absorption rates of a given drug should be the same for a given route of administration. - The differences in absorption rates are not caused by differences in the absorption pattern but by differences in the rate of drug release. - These differences in absorption rates obtained for one and the same drug, but in different dosage forms for the same route of administration, are “apparent” absorption rates. - This is because the true absorption rate is overlapped by release characteristics. - An apparent change in absorption rate will be obtained if the dissolution rate or liberation rate of the drug is slower than the unrestricted absorption rate of the pure drug in solution. - Absorption difficulties are encountered either with drugs of low solubility (solubility < 0.3 percent) or with those which are released extremely slowly from the dosage form. - In both cases, dissolution becomes the absorption rate-limiting step. - **Diagram:** - Shows a schematic of drug solubility and how it relates to absorption, dissolution and systemic circulation. ## Selected References 1. Barker, H.: The Role of Pharmaceutics in Drug Therapy, Australas. J. Pharm. 49:533 (1968). 2. Carstensen, J. T.: Theoretical Aspects of Interfacial and Surface Effects in the Dissolution of Drug Substances and Dosage Forms, 132nd Annual APhA Meeting, San Antonio, February 16-21, 1985. 3. Garrett, E. R.: Physico-Chemical Factors: Drug Systems Affecting Availability and Reliability of Response, J. Am. Pharm. Assoc. NS9:110 (1969). 4. Mitchell, A. G.: Pharmaceutical Factors Affecting Drug Availability, Australas. J. Pharm. 47:559 (1966). 5. Münzel, K.: Der Einfluss der Formgebung auf die Wirkung eines Arzneimittels. In: Progress in Drug Research, Karger, S., Editor, Birkhäuser Verlag, Basel-Stuttgart, 1966, p. 204. 6. Plakogiannis, F. M. and Cutie, A. J.: Basic Concepts in Biopharmaceutics, Brooklyn Medical Press, Brooklyn, Ν.Υ., 1977. 7. Polderman, J., Editor: Formulation and Preparation of Dosage Forms, Elsevier-North-Holland Biomedical Press, Amsterdam-New York-Oxford, 1977. 8. Ritschel, W. A.: Angewandte Biopharmazie, Wissenschaft-liche Verlagsgesellschaft, Stuttgart, 1973, pp. 52, 281. 9. Ritschel, W. A.: Physicochemical and Pharmaceutical Properties of Drugs and Dosage Forms Influencing the Results of Phase I Studies. In: Advances in Clinical Pharmacology, Kuemmerle, H. P., Shibuya, T. K. and Kimura, E., Editors, Urban and Schwarzenberg, Munich-Vienna-Baltimore, 1977, p. 116. 10. Swarbrick, J., Editor: Current Concepts in the Pharmaceutical Sciences: Dosage Form Design and Bioavailability, Lea and Febiger, Philadelphia, 1973. ## Pediatric Pharmacokinetics - The principles of biopharmaceutics and pharmacokinetics are based on a number of aspects of physiology. - The process of development has an impact upon each of the "phases" of drug disposition: - Absorption, distribution, metabolism, - Excretion - And, in some instances, on drug effect (e.g., response) as well. - A better understanding of the various physiological variables regulating and determining the fate of drugs in the body and their pharmacologic effects has dramatically improved both the safety and efficacy of drug therapy for: - Neonates, infants, children, and adolescents. - This understanding has largely resulted from data accumulated over the last 20 years and resulted from: - Guided clinical experience in pediatric drug therapy, - Most importantly, carefully conducted pediatric clinical trials of both old and new drugs. - Development, per se, represents a continuum of biologic events that enable adaptation, somatic growth, neurobehavioral maturation, and eventually reproduction. - The impact of development on the pharmacokinetics of a given drug is determined, to a great degree, upon age-related changes in body composition: - Body water spaces, circulating plasma protein concentrations - And the acquisition of function of organs and organ-systems which are important in determining drug metabolism (e.g., the liver) and excretion (e.g., the kidney). - It is often convenient to classify pediatric patients on the basis of postnatal age for providing drug therapy (e.g., neonate ≤ 1 month of age; infant = 1 to 24 months of age; children = 2 years to 12 years of age; and adolescents = 12 to 18 years of age) - It is important to recognize that changes in physiology which characterize development may not correspond to these age-defined "breakpoints" and also are not linearly related to age. - In fact, the most dramatic changes in drug disposition occur during the first 18 months of life where the acquisition of organ function is most dynamic. - The pharmacokinetics of a given drug may be altered in pediatric patients consequent to intrinsic (e.g., gender, genotype, ethnicity, inherited diseases) and/or extrinsic (e.g., acquired disease states, xenobiotic exposure, diet) factors which may occur during the first two decades of life. - Selection of an appropriate drug dose for a neonate, infant, child, or adolescent not only requires an understanding of the basic pharmacokinetic and pharmacodynamic properties of a given compound but also how the process of development might impact upon each facet of drug disposition. - It is most useful to conceptualize pediatric pharmacokinetics by examining the impact of development on those physiological variables which govern drug absorption, distribution, metabolism, and excretion ### Drug Absorption - The rate and extent of gastrointestinal (GI) absorption is primarily dependent upon pH-dependent passive diffusion and motility of the stomach and small intestine, both of which control transit time. - In term (i.e., fully mature) neonates, the gastric pH ranges from 6 to 8 at birth and drops to 2 to 3 within the first few hours. - After the first 24 hours of extrauterine life, the gastric pH increases to approximately 6 to 7 consequent to immaturity of the parietal cells. - A relative state of achlorhydria remains until adult values for gastric pH are reached at 20 to 30 months of age. - In the neonate, GI transit time is prolonged consequent to reduced motility and peristalsis. - Gastric emptying is both irregular and erratic, and only partially dependent upon feeding. - Gastric emptying rates approximate adult values by 6 to 8 months of age. - During infancy, intestinal transit time is generally reduced relative to adult values consequent to increased intestinal motility. - In the neonate and young infant, additional factors may play a role in intestinal drug absorption: - Increased permeability, immature biliary function, high levels of ß-glucuronidase activity, and variable microbial colonization - The developmental changes in GI function/structure in the newborn period and early infancy produce alterations in drug absorption which are quite predictable. - In general, the oral bioavailability of acid-labile compounds (e.g., beta-lactam antibiotics) is increased while that of weak organic acids (e.g., phenobarbital, phenytoin) is decreased. - For orally administered drugs with limited water solubility (e.g., phenytoin, carbamazepine), the rate of absorption (i.e., t_max) can be dramatically altered consequent to changes in GI motility. - In older infants with more rapid rates of intestinal drug transit, reductions in residence time for some drugs (e.g., phenytoin) and/or drug formulations (e.g., sustained-release theophylline) can reduce the extent of absorption (i.e., decreased bioavailability). - In the newborn and young infant, both rectal and percutaneous absorption is highly efficient for properly formulated drug products. - The bioavailability of many drugs administered by the rectal route (e.g., diazepam, acetaminophen) is increased not only consequent to efficient translocation across the rectal mucosa but also reduced presystemic drug clearance produced by immaturity of many drug metabolizing enzymes in the liver. - Both the rate and extent of percutaneous drug absorption is increased consequent to a thinner and more well hydrated stratum corneum in the young infant. - As a consequence, systemic toxicity can be seen with percutaneous application of some drugs (e.g., diphenhydramine, lidocaine, corticosteroids, hexachlorophene) to seemingly small areas of the skin during the first 8 to 12 months of life. - In contrast to older infants and children, the rate of bioavailability for drugs administered by the intramuscular route may be altered (i.e., delayed t_max) in the neonate. - This developmental pharmacokinetic alteration is the consequence of relatively low muscular blood flow in the first few days of life, the relative inefficiency of muscular contractions (useful in dispersing an IM drug dose,) and an increased percentage of water per unit of muscle mass. - Generally, intramuscular absorption of drugs in the neonate is slow and erratic with the rate dependent upon the physicochemical properties of the drug and on the maturational stage of the newborn infant. - **Table:** Show a table with neonates, infants, and children with comparisons of gastric emptying time, gastric pH, intestinal motility, intestinal surface area, microbial colonization, biliary function, muscular blood flow, skin permeability, and possible pharmacokinetic consequences. ### Plasma Protein Binding and Drug Distribution - During development, marked changes in body composition occur. - These changes include: - Total body water (TBW), - Extracellular water (ECW), - Body fat "pools" - **Diagram:** Show a comparison of % of body water, extracellular water and body fat in a line graph from birth to 40 years. - The most dynamic changes occur in the first year of life with the exception of total body fat which in males is reduced by approximately 50% between 10 and 20 years of life. - In females, this reduction is not as dramatic, decreasing from approximately 28 to 25% during this same period. - It is also important to note that adipose tissue of the neonate may contain as much as 57% water and 35% lipids, whereas values in the adult approach 26.3% and 71.7%, respectively. - In the neonate, the free fraction of drugs which are extensively (i.e., >60%) bound to circulating plasma proteins is markedly increased, largely due to lower concentrations of drug binding proteins (i.e., a lower number of binding sites), reduced binding affinity (e.g., lower binding affinity for weak acids to fetal albumin, presence of acidic plasma pH and endogenous competing substrates such as bilirubin, free fatty acids). - This is exemplified by phenytoin, a weak acid which is 94 to 98% bound to albumin in adults (i.e., free fraction = 2 to 4%) but only 80 to 85% bound in the neonate (i.e., free fraction = 15 to 20%). - Consequent to developmental immaturity in the activity of hepatic microsomal enzymes which are responsible for phenytoin biotransformation, compensatory clearance of the increased free fraction does not occur, thereby producing an increased amount of free phenytoin in the plasma and CNS. - This particular age-dependent alteration in drug binding functionally reduces the total plasma phenytoin level associated with both efficacy and toxicity in the newborn, as compared to older infants and children where phenytoin protein binding is normal. - Reduced plasma protein binding associated with absolute and relative differences in the sizes of various body compartments (e.g., total body water, extracellular fluid, composition of body tissues) frequently influences the apparent volume of distribution for many drugs and also influences their localization (i.e., both uptake and residence) in tissue. - As illustrated by the examples contained in Table 24-3, the apparent volume of distribution of small molecular weight compounds which are not extensively bound to plasma proteins (e.g., ampicillin, cefotaxime, gentamicin) corresponds to age-related alterations in the total body water space and extracellular fluid pool (Figure 24-1). - In contrast, the apparent volume of distribution for digoxin, a drug extensively bound to muscle tissue, does not decrease during the first years of life but rather increases to values (i.e., 10-15 L/kg for infants) which exceed those reported for adults (e.g., 5 to 7 L/kg), alterations that reflect both age-related changes in body composition and the affinity of digoxin for its binding sites. - **Table:** Show a table comparing neonates, infants, and children comparing plasma albumin, fetal albumin, total proteins, total globulins, serum bilirubin, serum free fatty acids, blood pH, adipose tissue, total body water, extracellular water, endogenous maternal substances (ligands), and possible pharmacokinetic consequences. ### Drug Metabolism - In general, most of the enzymatic activities responsible for metabolic degradation of drugs are reduced in the neonate. - Certain phase I biotransformation reactions (e.g., hydroxylation) appear to be more compromised than others (e.g., dealkylation reactions). - This is reflected by prolonged clearance of compounds such as phenytoin, phenobarbital, diazepam, lidocaine, meperidine, and indomethacin, during the first two months of life. - Phase II reactions are also unevenly reduced with sulfate and glycine conjugation activities present at near adult levels during the first month of life as opposed to glucuronidation (i.e., the activity of specific UDP glucuronosyltransferase isoforms) which is reduced as reflected by prolonged elimination of chloramphenicol (Table 24-3) in the neonate. - It must be recognized that developmental differences in hepatic drug metabolism occur consequent to reductions in the activity of specific drug metabolizing enzymes and their respective isoforms. - For most enzymes, the greatest reduction of activity is seen in premature infants where immature function may also accompany continued organogenesis. - As reflected by an examination of the ontogeny of important drug metabolizing enzymes as summarized in Table 24-4, it is apparent that maturation of activity is enzyme, and in some cases, isoform-specific. - It is also important to note that for enzymes which are polymorphic in their expression (i.e., more than one phenotype for activity), development per se may produce a discordance between the phenotype and genotype. - This is exemplified by N-acetyltransferase-2 (NAT2) where reduced enzyme activity results in over 80% of infants being classified as the poor-metabolizer phenotype during the first two months of age. - As denoted in Table 24-4, the activity of selected phase I and phase II enzymes in young infants can exceed that for adults. - The potential pharmacologic implications of this particular developmental alteration in drug metabolism is exemplified by examining the impact of age on the predicted steady state plasma concentrations of theophylline (a predominant CYP1A2 and xanthine oxidase substrate) from a fixed dose of the drug (Figure 24-2). - In the first two weeks of life, the activity of all of the cytochromes P450 and other enzymes (e.g., xanthine oxidase) responsible for theophylline biotransformation is virtually absent, leaving renal excretion of unchanged drug and trans-methylation of theophylline to caffeine as the predominant clearance pathways. By 3 to 6 months of postnatal age, CYP1A2 ontogeny results in activity of the enzyme which can exceed adult levels, thus increasing the plasma clearance of theophylline to maximum values as reflected in Figure 24-2. - While there is considerable evidence for dynamic, developmental regulation of drug-metabolizing enzymes reflected by pharmacokinetic data in pediatric patients, it is not generally known what is responsible for these changes in activity. - In the case of some enzymes (e.g., CYP1A2, CYP3A4), age-associated changes in activity appear to temporally correspond to periods of rapid somatic growth and/or sexual maturation, thus implying a role for neuroendocrine regulation (e.g., growth hormone, sex hormones). - As discussed elsewhere (see Chapters 13 and 39), pharmacogenetics may modulate the "pattern" of developmental differences in drug metabolism, especially for enzymes and transporters that are polymorphically expressed. - Finally, certain disease states that present in childhood (e.g., cystic fibrosis, sickle cell anemia, Down syndrome) may alter the developmental profile for activity of drug-metabolizing enzymes by virtue of disease modulation of activity as compared to normal infants and children. - As expected, age-related differences in the activity of drug metabolizing enzymes can have dramatic clinical implications for dose and dose interval selection. - An understanding of the basic clinical pharmacology of a given drug (often available from studies conducted in older children or adults), the ontogeny of drug metabolizing enzymes (Table 24-4) and of the other physiological alterations which occur during development that potentially impact hepatic drug metabolism (Table 24-5) can enable prediction of the possible pharmacokinetic consequences summarized in Table 24-5. - Determination of the developmental "breakpoints” for the activity of drug metabolizing enzymes can also enable effective guidance of drug dosing and/or the study of new drugs by eliminating arbitrary age-based categories (e.g., infant, child, and adolescent) which may or may not have anything to do with the competence of a specific drug metabolizing enzyme. - **Table:** Show a table of developmental patterns for the ontonogeny of important drug metabolizing enzymes in humans. ### Renal Drug Excretion - At birth, the kidney is anatomically and functionally immature. - **Diagram:** Show the ontogeny of glomerular filtration in term and preterm infants. - The acquisition of renal function depends, more than any other organ, on gestational age and postnatal adaptations. - In the preterm infant, renal function is dramatically reduced, largely due to the continued development of functioning nephron units (i.e., nephrogenesis). - In contrast, the acquisition of renal function in the term neonate represents, to a great degree, recruitment of fully developed nephron units. - In both term neonates and preterm infants who have birth weights >1500 grams, glomerular filtration rates increase dramatically during the first two weeks of postnatal life (Figure 24-3). - This particular dynamic change in function is a direct result of postnatal adaptations in the distribution of renal blood flow (i.e., medullary distribution to corticomedullary border), resulting in dramatic recruitment of functioning nephron units. - In addition, there is a situation of glomerular/tubular imbalance due to a more advanced maturation of glomerular function. - Such an imbalance may persist up to 6 months of age where both tubular and glomerular function approach normal values for adults. - **Table:** Show a table comparing neonates, infants, and children with comparisons of liver/body weight ratio, cytochromes P450 activity, blood esterase activity, hepatic blood flow, phase II enzyme activity, metabolic rates, presystemic clearance, total body clearance, and inducibility of enzymes. - The ontogeny of renal function and the potential pharmacokinetic consequences which occur during development are summarized in Table 24-6. - The fact that the ontogeny of renal function has been the most well characterized of any organ responsible for drug elimination makes it possible to accurately predict the potential impact of development on the elimination characteristics of drugs which are predominantly excreted by the kidney. - This is well illustrated by a recent study of famotidine, an H₂ receptor antagonist which in older children and adults is approximately 80% excreted unchanged in the urine. - A comparison of the pharmacokinetics of famotidine in neonates and older children is presented in Table 24-7. As illustrated by these data, the renal clearance of famotidine in children was approximately five-fold higher than that observed in neonates; populations where the average glomerular filtration rates would be expected to be approximately 100 and 20 ml/min/1.73 m², respectively. - As well, correlations between postnatal age, renal function status (i.e., glomerular filtration rate and tubular secretory capacity), and drug clearance have been demonstrated for aminoglycoside antibiotics, vancomycin, beta-lactam antibiotics, and ranitidine, all of which are predominantly excreted via renal mechanisms. ### Scaling of Clearance Based on Ontogeny - The pattern reflected by the ontogeny of a drug-metabolizing enzyme and/or physiologic indicator of renal function (e.g., glomerular filtration rate) now enables more refined approaches for scaling drug clearance as opposed to traditionally used allometric approaches based upon relative proportionality of body size and/or liver weight as compared to adults (Figure 24-4). - These newer approaches (described in detail by Alcorn and McNamara; see Reference 1) are based upon the determination of an "infant scaling factor” that is derived from information describing the metabolism of a given drug (e.g., Vmax, Km), physiologic data profiling the ontogeny of organ function (in the case of the kidneys), and, for drugs that are metabolized by one or more enzymes, the rate/pattern of acquisition of activity from birth through adulthood. - Generally, these new approaches provide reasonable concordance between predicted and observed clearance values early in life (i.e., 0–3 months) when intersubject variability in the activity of a drug-metabolizing enzyme may be lower (as compared to older infants and children) consequent to ontogeny and also for drug-metabolizing enzymes with lower normal interindividual variability in activity and which are monomorphically expressed. - **Diagram:** Show a line graph of scaled activity as a fraction of adult values in relation to age. - As illustrated by the aforementioned sections of this chapter, the physiological changes which occur consequent to the process of development are capable of altering the determinants of both dose size (i.e., apparent volume of distribution) and dose frequency (i.e., drug clearance). Ideally, pediatric dose selection for any drug should consider the potential impact of both normal and abnormal physiology (i.e., that induced by disease states) on the physiologic determinants of drug disposition at a given point in time. - In a perfect clinical setting, this would be accomplished through individualization of the dose regimen based upon patient-derived pharmacokinetic parameters (e.g., half-life, apparent volume of distribution, total plasma clearance). - The pediatric dose for a given drug could then be calculated to achieve either desired target plasma concentrations or alternatively, a drug “exposure” similar to adults as reflected by the dose-normalized AUC. - While this may be possible for some drugs whose plasma concentrations are either routinely measured on a clinical basis (e.g., aminoglycoside antibiotics, anticonvulsants, chloramphenicol, cyclosporine, tacrolimus, methotrexate, theophylline, caffeine) or alternatively whose pharmacokinetic characteristics were defined in pediatric subjects