Practical pharmacokinetics:what do you really need to know?

E S Starkey,1 H M Sammons2

1Derbyshire Children’s Hospital,Derby, UK2Division of Medical Sciences &Graduate Entry Medicine, Schoolof Medicine, University ofNottingham, Royal DerbyHospital Centre, Derby, UK

Correspondence toDr E S Starkey, DerbyshireChildren’s Hospital, Derby,DE22 3NE, UK;elizabeth.starkey@nhs.net

Received 20 August 2013Accepted 11 July 2014

To cite: Starkey ES,Sammons HM. Arch Dis ChildEduc Pract Ed PublishedOnline First: [please includeDay Month Year]doi:10.1136/archdischild-2013-304555

ABSTRACTHaving some understanding of pharmacokineticsis important for all clinicians when prescribingmedications. Key elements to effective and safeprescribing include making sure that we don’tunderdose a medication making it ineffective,but also do not overprescribe a treatment knownto cause toxic effects. In paediatrics, there aresignificant physiological and developmentaldifferences that add to the challenges of safeprescribing. This article aims to provide theclinician with some basic paediatricpharmacokinetic principles with clinical examplesto aid their prescribing skills.

INTRODUCTIONHaving some understanding of pharma-cokinetics is important for clinicianswhen prescribing. Key elements to effect-ive and safe prescribing include ensuringthat we don’t underdose drugs makingthem ineffective, while not overprescrib-ing and causing toxicity. In paediatrics,significant physiological and developmen-tal differences add to these challenges.This article aims to provide clinicianswith basic paediatric pharmacokineticprinciples and examples to aid theirunderstanding.

IMPORTANT PHARMACOKINETICPARAMETERS AND THEIR CLINICALRELEVANCEPharmacokinetics (PK) describes thecourse of a drug when it enters the body,including absorption, distribution, metab-olism and excretion. Pharmacodynamics(PD) refers to the effect the drug has onthe body.PK allows us to understand the profile

of drug concentration over time and thelinks to clinical practice. It allows us torecommend drug-dosing regimens or fornovel paediatric drug therapies, providesus with knowledge to prescribe safely andeffectively. The important parametersinvolved are discussed below.

Volume of distributionVolume of distribution (Vd) representsthe hypothetical volume that the totaldose administered would need to occupy(if uniformly distributed), to provide thesame concentration as it currently is inblood plasma. It is calculated by dividingthe amount of drug by the plasmaconcentration.A small Vd indicates that the drug mainly

stays within the systemic circulation,whereas a large Vd means a drug is well dis-tributed into other peripheral compart-ments. Knowledge of Vd can be used todetermine loading doses of drugs requiredto reach target concentrations and to predictexpected drug concentrations produced byloading doses. Loading doses can be calcu-lated from the product of target concentra-tion and Vd, for example, the gentamicindose in a 1 kg neonate to achieve a peakconcentration of 10 mg/L where the knownVd is 0.5 L/kg would be 10 mg/L×0.5 L/kg×1 Kg=5 mg1. However, in practice, weoften do not know the Vd of given drugs ingiven patients, particularly in neonates whenthe Vd changes rapidly over the first fewweeks of life as extracellular fluid volumedecreases.

ClearanceTotal body clearance is the intrinsicability of the body to remove a drugfrom the plasma/blood, and is the sum ofdrug clearance by each organ. For manydrugs this is equal to hepatic plus renalclearance. Renal clearance is the clearanceof an unchanged drug in the urine,whereas liver clearance can occur via bio-transformation to a metabolite/metabo-lites with subsequent excretion in urineand/or excretion of the unchanged druginto the biliary tract.When drugs are administered on a

regular basis, concentrations will increaseuntil the absorption or infusion rate isbalanced by the elimination rate. This is

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the steady-state concentration (Css) (figure 1).Clearance is the pharmacokinetic parameter that deter-mines the maintenance dose (MD) required to reach acertain steady-state concentration, whereMD=Css×Cl, for example, the maintenance dose ofan intravenous aminophylline infusion to achieve atheophylline level of 10 mg/L in a 20 kg child whereclearance is 0.087 mg/kg/h2 is 10 mg/L×(0.087×20)=17.4 mg/h. This formula can be applied to any routeof administration. If a drug is given as regular boluses,the ‘average’ target Css is used as steady-state fluctuatesbetween the peak and trough, and the dosing interval(π) is also added into the equation. For oral medica-tions, bioavailability also needs to be taken into consid-eration so MD=(avCss×Cl×π)/bioavailability.

Half-lifeHalf-life is another pharmacokinetic parameter, and isthe time taken for the serum drug concentration todecrease by half. It can be calculated from the Vd andclearance (where half-life (t1/2)=(0.693×Vd)/Clearance). It can be used to determine the time ittakes to achieve steady-state, and the time to be com-pletely eliminated. It takes around 3–5 times thedrugs’ half-life to reach steady-state, and the same forit to be completely eliminated. For instance, the t1/2 ofintravenous midazolam is approximately 1.1 h in3–10 year olds,3 therefore, it takes around 3.3 to5.5 h to reach steady-state.Half-life can also help clinicians to establish appro-

priate drug dosing intervals. When medications aregiven every half-life, the plasma concentration will

fluctuate twofold over the dosing interval (figure 1).If a drug is given more frequently than the half-life,fluctuations in peaks and troughs will be smaller. Bycontrast, when dosed at less than the half-life, lowerdrug accumulation occurs with greater fluctuation inthe peak and trough. The effective concentration andthe safety profile of the drug needs to be consideredto assess if large fluctuations are acceptable, forexample, a higher once-daily gentamicin dose isacceptable despite its short half-life of approximately3 h.4 It produces higher peak levels than the standardregime and this in turn increases the rate and extentof bacterial cell death, as well as lengthening the post-antibiotic effect (suppression of bacterial regrowth)without increasing the risk of any drug toxicity.5

For drugs with a half-life <6 h, it is sometimes notpractical to give frequent doses, so sustained releaseformulations are given if a steady serum concentrationis necessary (eg, theophylline).For drugs with a very long half-life (eg, phenobar-

bital), once-daily treatment may be appropriate,however, a loading dose may be required to reachsteady-state quickly. In neonates, the t1/2 of phenobar-bital is 67–99 h,4 so without a loading dose it couldtake 8–20 days to reach steady-state. Although drughalf-lives are quoted in the literature, these representaverage values mainly in adults, and should be usedcautiously.The PK principles outlined above assume that the

drug follows first-order or linear PK characteristics.This means that the steady-state concentrationchanges in direct proportion to a dose alteration.However, for some drugs, the relationship is morecomplex. For example, phenytoin saturates metabolis-ing enzymes at clinical doses. Subsequent increases indosing cause a disproportionate elevation of thesteady-state concentration. This is known as zeroorder or saturated kinetics.

BioavailabilityWhen a drug is given intravenously, the entire doseadministered enters the systemic circulation and issubsequently distributed. For any other route, thedrug must overcome chemical, physical, mechanicaland biological barriers, and the percentage that entersthe systemic circulation is the drug’s bioavailability.Drugs taken orally are absorbed from the gastro-

intestinal tract into the liver via the portal circulation,before reaching the systemic circulation. Most drugsundergo some degree of metabolism in the liverbefore reaching the central compartment. This isknown as first-pass metabolism. Those drugs undergo-ing a large first-pass effect, for example, propranolol,have lower bioavailability.Bioavailability is important because it allows us to

understand how drug (eg, formulation, drug solubil-ity) or human factors (eg, comorbidities, diet) canalter the dose-exposure relationship. For example, the

Figure 1 This graph shows a time concentration profile of adrug with a half-life of 11.5 h given by continuous infusion(solid line) and intermittent dosing every 12 h (dotted line). Thesteady-state is reached by 57.5 h (5 times the 11.5 h half-life).With the intermittent dosing, serum drug concentrationsincrease, after each dose, to a peak amount and then decline toa trough concentration before the next dose. Repeated dosingincreases the peak and trough concentrations due to drugaccumulation until steady-state is achieved. At steady-state, allthe peak and trough concentrations become equal andsteady-state is achieved to the same 57.5 h as the continuousinfusion. Note, as the half-life is similar to the dosing frequency,there is twofold difference between the peak and troughconcentrations. Adpated from Kraus.31

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bioavailability of digoxin given as tablets is 63% but75% in the paediatric elixir form.6 Bioavailability canalso affect apparent Vd and clearance by reducing theamount of drug that enters the bloodstream.

ABSORPTIONAbsorption is the process of drug movement from thesite of administration/application into the systemic cir-culation. There are a number of differences betweenchildren and adults attributable to normal growth anddevelopment.At birth, gastric pH is around neutral but drops to

pH 1–3 within a few hours. It returns to neutral by24 h where it remains for 1–2 weeks. Adult values forgastric acidity are reached only after age 2 years.7 Thishigher gastric pH results in decreased absorption ofacidic drugs, such as phenobarbital and phenytoin,but increases absorption of weak base or acid-labiledrugs, such as penicillins.8 9 Proportionally higherand lower oral doses, respectively, may be needed toachieve therapeutic plasma concentrations in neonatesand infants.Gastric emptying and intestinal motility are slower

in neonates and improve with increasing gestationalage.10 11 This may delay absorption in neonates andsmall infants12 13 Neonates also have an immaturebiliary system, producing less bile acids and pancreaticfluid. This reduces fat absorption and can affect theabsorption of lipophilic drugs,14 for example, diaze-pam and fat-soluble vitamins.Intramuscular absorption depends on skeletal

muscle blood flow which improves during childhood.Neonates have poor muscle contractions and muscledensity reducing bioavailability.15 Percutaneousabsorption is enhanced in childhood due to a largersurface area relative to body weight, increased skinhydration and perfusion. In neonates and younginfants absorption is further increased due to animmature epidermal barrier. This makes children,especially neonates, more prone to increased systemicabsorption and potential side effects of topical medi-cations. Past use of the topical disinfectant hexachlor-ophene in neonates caused neurotoxicity and death.16

Developmental changes in pulmonary structure andcapacity in young patients may also alter patterns ofinhaled drug absorption. In the rectum, a richer bloodsupply potentially allows increased drug absorption,but this can vary.17

DISTRIBUTIONDrug distribution is dependent upon the physico-chemical properties of the drug and also on patientspecific physiological factors. Understanding variablesaffecting distribution explains some of the variation indosing requirements required in different paediatricpopulations. Drug distribution is affected by changesin body composition. Neonates have a high total bodywater which decreases in adulthood (table 1).

Neonates also have less fat compared with adultsresulting in them having a higher water to fat ratio.This means that water-soluble drugs have a higher Vdin the neonate resulting in lower peak concentrationlevels when using the same drug dose/weight com-pared with adults. A greater loading dose per kilo-gram may be required compared with older children/adults to have a similar therapeutic effect. Forexample, the Vd of gentamicin in neonates is highercompared with older children/adults due to theincreased extracellular water. They, therefore, requirehigher doses per kilogram to produce adequate serumconcentrations.18 The lower fat content in neonatesresults in a decreased Vd for fat-soluble drugs thoughthe effect of this is not well understood.Changes in the composition and amount of circulat-

ing plasma proteins, such as albumin and α1-acidglycoprotein can also influence the distribution ofhighly protein-bound drugs, such as phenytoin andfurosemide. Neonates and infants have less totalplasma proteins which increases the free (active) frac-tion of drug.17 Additionally, endogenous compounds,like bilirubin, compete for protein binding contribut-ing to a higher free fraction of highly protein-bounddrugs. Conversely, sulfonamides are an example ofhighly protein-bound drugs which can displace biliru-bin in neonates leading to a risk of kernicterus.18

Other factors that may affect drugs distributioninclude changes in haemodynamic status, changes inacid–base balance, and permeability of cell mem-branes. These are particularly important when dealingwith severely ill patients, for example, those on extra-corporeal membrane oxygenation.19

METABOLISMIn general, most drugs are converted into more water-soluble compounds in order to be excreted from thebody. This can take place in several sites (eg, gastro-intestinal tract, skin, plasma, kidney, lungs), but mostare metabolised in the liver via hepatic enzymes inphase 1 and phase 2 reactions. Phase 1 involves alter-ing the structure of the drug, for example, by oxidationor hydrolysis. The major pathway is oxidation involv-ing the cytochrome P450-dependent (CYP) enzymes.Phase 2 reactions conjugate the drug to another

Table 1 Changes in body water with age. Adapted fromFriis-Hansen30

Totalbodywater (%)

Extracellularfluid (%)

Intracellularfluid (%)

Preterm neonate 85 60 25

Neonate 80 45 35

Infant 1 year 60 25 35

Adult 60 20 40

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molecule (eg, glucuronidation). Total cytochromeP450 content in the foetal liver is between 30% and60% of adult values, and approaches adult values by10 years of age.20 Different developmental patternshave been identified for CYP enzymes (figure 2). Someare active in the foetal liver (CYP3A7), others increaserapidly hours after birth (CYP2D6 and CYP2E1),while others develop more slowly in infancy(CYP1A2).16 Clinically, this means that drugs metabo-lised by the liver in newborns and small infants, tendto stay in the body longer. This, therefore, requireslower doses, longer dose intervals, or to give adequatetherapeutic concentrations and prevent toxicity.Phenytoin,21 chloramphenicol13 and caffeine22 areexamples of drugs showing slower neonatal metabol-ism. Historically, chloramphenicol was used to treatneonatal infections using adult doses of 12.5–25 mg/kgfour times a day. Large numbers developed cardiovas-cular collapse, irregular respiration and death—fea-tures known as grey baby syndrome. Neonates haveimmature levels of the enzyme converting chloram-phenicol to the excreted water-soluble chlorampheni-col glucuronide which, therefore, accumulates andcauses toxicity. Consequently, dosing in neonates hasbeen reduced to 12.5 mg/kg twice daily.23

In some circumstances, alternative metabolic path-ways are used in younger children. Paracetamol under-goes metabolism by glucuronidation and sulfation. Inneonates, glucuronidation is reduced, but there is,however, compensatory sulfation.24 With largeamounts of paracetamol, glucuronidation and sulfa-tion pathways become saturated, so paracetamol ismetabolised by CYP2E1. This produces toxic productsand subsequently liver damage. In neonates, immatur-ity of this pathway may produce less toxins sparingthem from liver damage.25

EXCRETIONFor many drugs and metabolites, the kidney is themost important route of excretion. The kidney has

three physiologic functions: glomerular filtration,tubular secretion and tubular reabsorption. Renalelimination of drugs is dependent on a balance ofthese. Some drugs are eliminated by glomerular filtra-tion (eg, aminoglycosides) and clearance correlateswell with glomerular filtration rate. Others are elimi-nated by proximal tubular secretion (eg, penicillins,furosemide). Tubular reabsorption of drugs alsoaffects total body clearance.Maturation of renal function is a dynamic process

beginning during fetal organogenesis. All three physio-logic functions of the kidney are decreased in newborns.The development of kidney structure and function isassociated with prolongation and maturation of thetubules, increase in renal blood flow and improvementof filtration efficiency. By around 12 months of age,these functions reach adult levels.19 Having someknowledge of renal development and anatomy is essen-tial in providing rational dose schedules for drugs exclu-sively eliminated via the kidneys. In general, the neonatewill need longer dose intervals than the infant/olderchild to maintain target concentrations. For example,the dose of benzylpenicillin changes from 25–50 mg/kg12 hourly in a neonate <7 days, 8 hourly in a 7–28 dayneonate and then 4–6 hourly in children over a monthold, reflecting the improving renal function andexcretion.23

INTERINDIVIDUAL VARIABILITYIt is known that different patients respond differentlyto the same medication. This is known as interindivi-dual variability. In children, it is complicated furtherby the impact of physiological development and mat-uration. A large amount of interindividual variabilityis caused by genetic variations in activity of drugmetabolism enzymes and transporters. CYP2D6 poly-morphism is used as an example. This enzyme meta-bolises a number of drugs including β blockers,antidepressants and codeine. Homozygous individualscharacteristically have negligible or no metabolism

Figure 2 Developmental differences in enzyme capacity. Adapted from: Kearns17 and Johnson.32

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and are ‘poor metabolisers’. If the drug is a ‘prodrug’,such as codeine (whose main analgesic effect is pro-duced by its major metabolite morphine), then littlebenefit will be produced, and increased side effectsmay be experienced due to delayed excretion. Thosewith gene duplications or multiplications aredescribed as ’ultrarapid metabolisers’, they are at riskof reduced effects or toxicity from quick metabolismdepending on the drug. Case reports in children post-adenotonsillectomy highlight fatalities from respira-tory depression secondary to codeine use in CYP2D6‘ultrametabolisers’, due to increased morphine pro-duction.26 There have also been similar reports inbreastfeeding neonates whose mothers were takingcodeine and were CYP2D6 ‘ultrametabolisers’.27

Underlying disease may affect the disposition ofdrugs and impact drug variability. For example, clear-ance of most drugs is thought to be higher in childrenwith cystic fibrosis (CF), resulting in higher dosagesbeing required for therapeutic benefit, and to achievesimilar serum drug concentrations to children withoutCF.28 Tobramycin dosing increases from 2–2.5 mg/kgthree times a day to 8–10 mg/kg three times a day toprovide optimal bacterial penetration within CF bron-chial secretions.23 Many other factors can influenceinterindividual variability in drug response includingethnicity, organ function, concomitant medicationsand drug interactions.

THERAPEUTIC DRUG MONITORING (TDM)TDM measures drug concentrations and uses PK prin-ciples to allow individualised drug dosing withminimal toxicity and maximal efficacy. A number ofcriteria are required for TDM, as shown in the box 1.In clinical practice, to interpret drug concentrations,basic information about the sample and patient arerequired, as well as some understanding of the drugsdisposition and pharmacology. Timing of samplesplays a large part in interpretation. Levels should onlybe taken once the drug has reached its steady-stateunless there are concerns regarding toxicity. In

general, trough levels measured just prior to drugadministration provide accurate interpretation of drugconcentrations. Peak levels are less accurate due toindividual variability and are reserved for treatmentswith short half-lives where peak levels are associatedwith efficacy or toxicity, for example, gentamicin.

IMPORTANCE OF PHARMACOKINETICS INPAEDIATRIC CLINICAL STUDIESSince the paediatric EuropeanUnion regulations cameinto force in 2007, it is mandatory for pharmaceuticalcompanies to submit a Paediatric Investigation Planoutlining how they will study their new drug in chil-dren. This has increased the number of paediatrictrials, including more PK studies allowing moredefined paediatric dosing regimens for new drugs.29

Different techniques, such as population PK (usinglarge numbers of children with a condition but lessblood samples) and PK/PD modelling (using statisticalvalidated models for predicting the effect and efficacyof a drug) are now well established. This avoids chil-dren being exposed to the unethical practice of exces-sive numbers and large volumes of blood samplingseen in adult PK studies. Despite this, there are stillsignificant gaps in our knowledge, especially in theolder medications in current practice. The paediatricregulation introduced a paediatric-use marketingauthorisation (PUMA) which gives drug companiesincentives to develop new paediatric indications orformulations appropriate for children of all ages.Since 2007, there has been only one PUMA grantedfor buccal midazolam in seizures.29 The ultimate goalof providing infants and children with safe and effect-ive drug therapy can only be made possible by specif-ically evaluating PK as well as drug efficacy and safetyin this population.

CONCLUSIONSHaving some knowledge of PK is important for anyclinician, however, in children, there is the addedcomplexity of developmental influence on drug

Learning points

▸ Pharmacokinetics is the study of how a drug isaffected as it passes through the body by absorption,distribution, metabolism and elimination.

▸ Growth and development of children impacts in mul-tiple ways on pharmacokinetics.

▸ A therapeutic agent administered other than intra-venously must overcome chemical, physical, mechan-ical and biological barriers in order to be absorbed.

▸ Knowledge about the impact of developmental differ-ences is important in providing adequate drug dosingand frequency.

Box 1 Criteria for therapeutic drug monitoring

▸ Good correlation between serum concentrations andpharmacological effect.

▸ A narrow margin between serum concentrations thatcause toxic effects and those that produce thera-peutic effects.

▸ Marked pharmacokinetic intra and interindividualvariability.

▸ The pharmacological effects of drugs are not readilymeasurable.

▸ A rapid and reliable method for the analysis of thedrug.

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disposition. Understanding these differences willhopefully allow clinicians to be better equipped tooptimise the care of their patients and ultimatelyprovide safer and more effective prescribing.

Contributors ES researched and compiled the manuscript. HMShas provided critical review of the manuscript for submission.

Competing interests None.

Provenance and peer review Commissioned; externally peerreviewed.

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Test your knowledge

One or more of the answers can be correct1. Which factors cause neonates to have increased drug

absorption through the skin compared with adults?A. a thinner epidermisB. a larger surface areaC. reduced skin blood flowD. improved skin perfusionE. less subcutaneous tissue

2. Half-life determines:A. the loading doseB. the time to reach steady-stateC. the drug concentration at steady-state during con-

stant dosingD. duration of action of a single doseE. the fluctuation in plasma drug concentration

during a dosing interval3. Which of the following is true with regards to volume

of distribution:A. Equals the total amount of drug in the body

divided by the concentration found in the plasmaB. A large volume of distribution (Vd) implies a drug

primarily resides in the systemic circulationC. Neonates have a larger Vd for hydrophilic drugsD. A larger Vd requires a lower loading dose of a

drugE. Neonates have a lower Vd with fat-soluble drugs

4. Which is true about renal elimination in children?A. Affected by immature glomerular filtrationB. GFR is similar to adults by 12 months of ageC. Drug dosing intervals are usually increased com-

pared with neonatesD. Penicillin is eliminated by proximal tubule

secretionE. Glomerular filtration rate affects elimination of

furosemide.Answers are at the end of the references.

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24 Miller RP, Roberts RJ, Fischer LJ. Acetaminophen eliminationkinetics in neonates, children and adults. Clin Pharmacol Ther1976;19:284–94.

25 Ogilvie JD, Rieder MJ, Lim R. Acetaminophen overdose inchildren. CMAJ 2012;184:1492–623. Paracetamol

26 Kelly LE, Rieder M, van den Anker J, et al. More codeinefatalities after tonsillectomy in North American children.Pediatrics 2012;129:e1343–7.

27 Koren G, Cairns J, Chitayat D, et al. Pharmacogenetics ofmorphine poisoning in a breastfed neonate of acodeine-prescribed mother. Lancet 2006;368:704.

28 Rey E, Tréluyer JM, Pons G. Drug disposition in cystic fibrosis.Clin Pharmacokinet 1998;35:313–29.

29 The European Medicines agency. http://www.ema.europa.eu/ema. [accessed 23 Oct 2013].

30 Friis-Hansen B. Body water compartments in children: changesduring growth and related changes in body composition.Pediatrics 1961;28:169–81.

31 Kraus D. Clinical Pharmacology. In: Curley MAQ,Moloney-Harmon PA. eds. Critical Care nursing of infants andchildren. Philadelphia: Saunders, 2001:425–42.

32 Johnson TN. The development of drug metabolising enzymesand their influence on the susceptibility to adverse drugreactions in children. Toxicol 2003;192:37–48.

ANSWERS TO THE QUIZ

Question 1(A) True; (B) True; (C) False; (D) True; (E) False.

Question 2(A) False; (B) True; (C) False; (D) True; (E) True.

Question 3(A) True; (B) False; (C) True; (D) False; (E) True.

Question 4(A) True; (B) True; (C) False; (D) True; (E) False.

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really need to know?Practical pharmacokinetics: what do you

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