John T. Wilson

Drug Excretion in Human Breast Milk

SummaryThe excretion of drugs in human breast milk is reviewed with regard to milk production, composition, feeding patterns and mechanisms of drug transfer into milk. Fundamental principles of breast milk excretion are used to construct a pharmacokinetic approach useful for the study of most drugs. An infant-modulated 3-compartment open model is proposed for drug distribution and elimination in the breast feeding woman. Milk/plasma drug concentration ratios are projected on the basis of pH partitioning. While some studies confirm these projections, other studies demonstrate a need to consider additional factors such as lipid solubility and protein binding characteristics of a drug in milk.Data are lacking for most drugs and hence dosing via milk or risk to the infant remains speculative. Very few pharmacokinetic studies of both milk and infant plasma were found. A review of selected drug classes cites available information as a basis for future studies. Few drugs are contraindicated in breast feeding women, but supportive data for either proscriptions or permissive statements are often lacking. A neglected but potentially serious infant risk — impaired behaviour and development — is discussed from the standpoint of emerging animal data.Conceptually valid and comprehensive studies on drug excretion in breast milk are needed if this valuable nutrient for infants is to be made available safely.

Use of psychoactive medication during pregnancy and possible effects on the fetus and newborn

Psychoactive drugs are those psychotherapeutic drugs used to modify emotions and behavior in the treatment of psychiatric illnesses. This statement will limit its scope to drug selection guidelines for those psychoactive agents used during pregnancy for prevention or treatment of the following common psychiatric disorders: schizophrenia, major depression, bipolar disorder, panic disorder, and obsessive-compulsive disorder. The statement assumes that pharmacologic therapy is needed to manage the psychiatric disorder. This decision requires thoughtful psychiatric and obstetric advice.

Dosing implications of altered gentamicin disposition in patients with cystic fibrosis

A pharmacokinetic approach was used for gentamicin dosing in 19 children and young adults with cystic fibrosis. A one-compartment open-model analysis of steady-state gentamicin pharmacokinetics revealed a significantly larger apparent volume of distribution and total plasma clearance for patients with CF as compared to a similar population of children without the disease. The increase in the apparent volume of distribution for patients with CF produced a larger daily gentamicin dose requirement to maintain similar steady-state levels as compared to children without the disease. Significant differences in the elimination rate constant and half-life for gentamicin were not found between these populations. Linear correlations between creatinine clearance and kel for gentamicin, and total body body weight and the apparent volume of distribution were demonstrated for children with varying degrees of stable renal function but not patients with CF. Altered gentamicin disposition peculiar to CF precludes application of currently used dosing nomograms or guidelines derived from normal populations, and emphasizes the need for individualized gentamicin therapy guided by a pharmacokinetic approach in these patients.

Single-dose pharmacokinetics of ibuprofen and acetaminophen in febrile children

The disposition of antipyretic drugs is central to the understanding of their action in children. Accordingly, the authors measured plasma levels of acetaminophen and ibuprofen in 153 febrile children for 6 hours after a single dose of either acetaminophen (12.5 mg/kg) or ibuprofen (5 or 10 mg/kg). Cmax occurred about 2 1/2 hours before maximum antipyresis, when plasma acetaminophen or ibuprofen was 25 to 50% less than Cmax. Most plasma level data fit a one‐compartment open model, and this suggests a pharmacodynamic basis for the observed lag between Cmax and maximum antipyretic response. Plasma levels (and AUC0→∞) of ibuprofen 10 mg/kg were less than expected for a two‐fold increase in dose. For acetaminophen, the tlog was less than ibuprofen, Ka was more than ibuprofen, and β was less than ibuprofen. The ibuprofen β was not dose dependent, but the Vd was dose and model dependent. In contrast, ibuprofen Clp was dose and model independent. Acetaminophen pharmacokinetics were similar to those previously reported. Initial temperature, race, gender, prior medications, or diagnosis did not confound the results for ibuprofen or acetaminophen. Accordingly, a pharmacodynamic basis is a more likely explanation for the initial temperature effects found previously for antipyretic drugs in children. Ibuprofen (5 and 10 mg/kg) AUC0→∞ was higher in the older (≥ 2.5 yrs) children and the Vd and Clp were lower in the older children, when discriminated by age or pharmacokinetic parameters. The observed dose dependency of AUC0→∞ and the effect of age on ibuprofen disposition must be considered if pharmacokinetic interpretations are used to develop the antipyretic dose of ibuprofen in children.

The Pharmacokinetics of Irbesartan in Hypertensive Children and Adolescents

An open‐label study was conducted to characterize the pharmacokinetics and antihypertensive response to irbesartan in children (1–12 years) and adolescents (13–16 years) with hypertension. Patients received single once‐daily oral doses of irbesartan 2 mg/kg (maximum of 150 mg once daily) for 2 to 4 weeks (nifedipine or hydrochlorothiazide). Plasma irbesartan concentrations were determined by a validated high‐performance liquid chromatography/fluorescence method from blood samples taken predose, up to 24 hours after dosing on Day1, and up to 48 hours after the final dose. The plasma concentration‐time profiles were similar between the 6‐ to 12‐year and the 13‐ to 16‐year age groups and to that previously determined from a study of adult subjects receiving 2 mg/kg (i.e., 150 mg) oral irbesartan once daily. Mean reductions in systolic/diastolic blood pressure were 16/10 mmHg at Day 28 with irbesartan monotherapy (n = 8). Irbesartan was well tolerated and maybe a treatment option for pediatric hypertensive patients.

Single‐Dose Pharmacokinetics of Bupropion in Adolescents: Effects of Smoking Status and Gender

Sustained‐release (SR) bupropion (Zyban®) is approved as a smoking cessation aid for adults. Since smoking often begins in adolescence, we determined the single‐dose pharmacokinetics of bupropion SR in 75 adolescent subjects ranging from 13 to 18 years old. Subjects self‐reported their smoking status. Urinary cotinine concentration was used to verify smoking status. Thirty‐seven subjects (18 males, 19 females) were classified as cigarette smokers and 38 were nonsmokers (19 males, 19 females). Fasted subjects received one tablet (150 mg) of bupropion SR, and plasma samples were collected before (0) and 1/2, 1, 2, 3, 4, 6, 8, 24, 48, and 72 hours after dosing. Plasma samples were analyzed for bupropion and its three major metabolites (hydroxybupropion and the aminoalcohol isomers, erythrohydrobupropion plus threohydrobupropion, ex‐pressed as a composite) by solid‐phase extraction, followed by LC/MS/MS. Factorial analysis of variance (ANOVA) was used to evaluate the effects of smoking and gender on pharmacokinetic parameters. Smokers and nonsmokers differed significantly (p <0.05) in age and urinary cotinine (p < 0.01) concentration but did not differ significantly in mean weight, height, body surface area, or body mass index. The pharmacokinetic (PK) parameters for bupropion and hydroxybupropion did not differ between smokers and non‐smokers, but differences were found between male and female subjects. Mean values for area under the plasma concentration versus time curve (AUC0→), volume of distribution (Vdβ) normalized to body weight, maximum plasma concentration (Cmax), and elimination half‐life (t1/2β) for bupropion were significantly (p < 0.05) greater in females than males, while clearance of bupropion normalized to body weight (CL/f) did not differ between males and females. Females also exhibited significantly (p < 0.05) larger values for hydroxybupropion mean AUC0→ and Cmax than males. The mean ratio of hydroxybupropion to bupropion AUC for adolescents was approximately 4 to 5, which is lower than that previously reported for adults. In conclusion, smoking status does not affect the single‐dose pharmacokinetics of bupropion SR in adolescents. However, females differ from males in several potentially important PK parameters for bupropion and its major metabolite, hydroxybupropion.

Concordance between Tramadol and Dextromethorphan Parent/Metabolite Ratios: The Influence of CYP2D6 and Non‐CYP2D6 Pathways on Biotransformation

Cytochrome P4502D6 (CYP2D6) activity has been shown to be a determinant of both the pharmacokinetics and pharmacodynamics of tramadol in adults. This study evaluated the association between CYP2D6 activity, as determined by dextromethorphan (DM) urinary metabolite ratio, and tramadol biotransformation in 13 children (7–16 years). CYP2D6 genotype was determined by XL‐PCR and PCR/RFLP. Phenotype was assessed by HPLC quantitation of DM and its metabolites from a 12‐ to 24‐hour urine collection following a single oral dose of DM. There was only a modest correlation between tramadol/M1 (metabolite 1)plasma concentration or AUC and the DM/dextrorphan (DX) urinary molar ratio in the study cohort; however, when subjects were segregated based on the number of functional CYP2D6 alleles, a much stronger relationship was observed for subjects with two functional alleles, with essentially no relationship evident in those individuals with one functional allele. Further evaluation of these data suggested that the CYP2D6‐mediated metabolite (M1) is formed to a lesser extent, and the formation of the non‐CYP2D6 product (M2) is more pronounced in subjects with one versus two functional alleles. Thus, the number of functional CYP2D6 alleles and the availability of alternative cytochromes P450 capable of metabolizing tramadol may explain the poor association between DM, a well‐characterized CYP2D6 probe, and tramadol in a population of CYP2D6 extensive metabolizers.

Integrated Pharmacokinetic–Pharmacodynamic Model for Acetaminophen, Ibuprofen, and Placebo Antipyresis in Children

A descriptive profile for antipyretic drug action has been documented for children. However, a linked pharmacokinetic–pharmacodynamic (PK/PD) model is central to the understanding of antipyretic drug action in febrile children. This was examined for previously reported data from 178 febrile children who received a single oral dose of acetaminophen (APAP) (12.5 mg/kg), ibuprofen (IBU) (5 or 10 mg/kg), or placebo. Rectal temperatures and plasma levels (μg/ml) of APAP and IBU were measured for up to 12 hr after drug administration. Nonlinear regression analyses were applied to these measurements and yielded simultaneous solutions of an integrated one-compartment PK, link, and SigmoidEmaxeffect model in 102/153 febrile children given APAP or IBU. The PK parameters (tlag,ka, β,T1/2β,AUC0–∞,Vd/F,andClp/F) were not different than those reported previously, except the APAPkawas significantly lower. The link component yieldedkeos of 0.58±0.06 (X±SE), 0.70±0.11 and 0.57 ± 0.11 hr-1for APAP, IBU05, and IBU10, respectively: the SigmoidEmaxcomponent yieldedEC50s (μg/ml) and sigmoidicity (γ) of 4.63±0.39 and 3.98±0.42 for APAP, 11.33±1.35 and 3.97±0.58 for IBU05 and 12.83±1.89 and 4.27±0.63 for IBU10. On visual inspection of the efficacy–time profiles of the febrile children, a number of them had an apparent linear function (slope; Δ°C/hr) and/or a sinusoidal cyclic function “confounding” standard approaches to PD analysis. Thus, the temperature profiles of 91/102 children given APAP or IBU required the addition of a slope (Δ°C/hr) and/or a sinusoidal cyclic function to the SigmoidEmaxcomponent to fit the data satisfactorily. All 22 children given a placebo also required a slope and/or a cyclic function in their PD model. The residual Δ°Cs (observed-predicted) of the placebo group were not significantly different from 0. Thus, no placebo antipyretic effect was observed. Dose dependency of IBUAUC0–∞was confirmed; doubling the dose from 5 to 10 mg/kg increased theAUC0→∞by only 1.5-fold. The confounding effect of initial temperature (Tempi) on antipyretic efficacy in all treatment groups except placebo was also confirmed to expose nonlinear pharmacodynamics. A significant (p=0.03) contribution ofTempi(but not age) on the value of the slope function was found. There was no consistent effect of age orTempi, on the cyclic component of the integrated model of antipyresis. In addition, a multiple linear relationship of age andTempiwas observed with a large number of the PK, link, and PD variables in those who received IBU. Dose, age, andTempiinteracted with β in a significant multiple linear relationship withAUC0–∞. The effects of IBU dose, age, andTempiare pervasive and cascade down the chain of events leading to the PD response. The etiology of pyresis may create the slope function, the magnitude of which may be partially due to the underlying disease. In some cases, the cyclic function may be explained by temperature regulation. Regardless of their cause, both confound analysis of drug action and make the simple, unmodified SigmoidEMaxeffect model less than satisfactory for interpretation of antipyretic drug effects. The influence of Tempion the magnitude of antipyretic drug response is also a finding with major impact on PD investigations of antipyretic medications. In children receiving IBU, dose and age are also confounders, in addition toTempi. A multiplicity of covariables must be taken into account when developing appropriate dosing regimens for these antipyretics in febrile children.

Paediatric Labelling Requirements

SummaryThe US Food and Drug Administration (FDA) has proposed new labelling regulations that describe alternative approaches for providing additional information to support labelling a drug, already approved for use in adults, for use in children. Therefore, the study of drugs in paediatric populations may now be encouraged. Paediatric pharmacokinetic studies are an important part of these trials. This action by the FDA may help resolve the ethical and technological concerns about the performance of clinical trials in children, and may render paediatric clinical trials more feasible. Most investigations in children are opportunistic in nature and their design is often constrained by a requisite noninvasive approach.Appropriately applied population-based techniques for both pharmacokinetic and pharmacodynamic data analysis may represent the most robust approach for generating a sufficiently large and accurate database for the use of new or old drugs in paediatric patients. Accordingly, this information, which is crucial for paediatric labelling of any drug product, must be obtained in infants and children if we are to truly individualise therapy for paediatric patients.The funding of 6 Pediatric Pharmacology Research Units by the US National Institutes of Health, and guidelines for application of pharmacokinetic methods to children may further contribute to the performance of paediatric clinical trials.

Flurbiprofen in Post‐Partum Women: Plasma and Breast Milk Disposition

The plasma and milk disposition of flurbiprofen (FB) was assessed in healthy women during the early post‐partum period after multiple doses of FB. The results confirmed that a pragmatic study design is an attainable requirement for definitive statements about the excretion of FB in transitional milk. Nine doses of FB (50 mg per dose) were administered during three days. Paired milk and plasma samples were obtained during this period of dosing as well as after the last dose. The plasma data were used to derive an equation, which was then used to simulate cumulative plasma profiles for multiple doses given at unequal time intervals. The observed data corresponded to the simulated cumulative profiles of FB in plasma. The plasma elimination half‐life of FB during early lactation was slightly prolonged (mean 4.8 hrs) as compared to reported values for normal adult men. The peak plasma concentrations of FB were comparable to those reported for healthy volunteers. In 10 of 12 women (3–5 days post‐partum) the FB concentration in breast milk was less than 0.050 μg/ml. In two women the milk concentrations of FB were 0.06, 0.07 and 0.07 μg/ml as found in only three samples. We conclude that, on the basis of dose found in milk, FB is safe for women breast feeding their infants in the early post‐partum period.