Pharmacokinetic considerations
| Absorption of medicines | Administration of medicines |
|---|---|
| Oral absorption in neonates can be altered by:Immature transporter expression and increased intestinal permeability. Slower gastric emptying at birth limits access of medicines to absorption sites. Reduced gastric acid secretion increases bioavailability of acid-labile drugs (eg, ampicillin) and decreases that of weakly acidic drugs (eg, phenobarbital), which are less able to exist in non-ionised form.3 Intestinal transit and transport processes mature by 4 months.3 | Medicines not formulated for children only available in solid dose forms that young children cannot swallow, in strengths that do not provide dose flexibility. Liquid medicines may contain excipients unsuitable for children, for example, alcohol, propylene glycol or tartrazine. Specific challenges in drug administration and absorption in children with surgical short bowel or jejunal feeding tubes. |
| Rectal absorption may be unreliable and affected by formulation, site of placement in rectal cavity and duration of retention (infants have increased rectal pulsatile contractions). Bioavailability can be increased in infants due to reduced ‘first pass’ hepatic metabolism.3 | Rectal route useful for child not tolerating oral medication or intravenous access not available. Rectal drug therapy not well accepted by UK patients and used infrequently in hospital practice. |
| Absorption from intramuscular injections in young children can be reduced due to low muscle mass and poor perfusion.3 However, intramuscular vitamin K at birth provides a depot to prevent deficiency bleeding (haemorrhagic disease of the newborn).21 | Intramuscular injections usually avoided in children due to pain and distress but may have a place for single doses.8 |
| Intravenous administration is used to avoid absorption problems and ensure rapid achievement of therapeutic levels, for example, for antibiotics in sepsis. | Difficulty maintaining intravenous access in small veins limits acceptability longer-term and central access may be needed. Specific technical requirements for intravenous administration, for example, need to account for displacement values when reconstituting and taking a portion of a vial; infusion fluids, volumes, rates must take into account age/weight/renal function. |
| Intraosseous route (infusion directly into bone marrow) is relatively easily accessible in children (due to ease of access to the anterior tibial marrow and vascularity of marrow) | Intraosseous used in emergencies when central vascular access cannot be achieved in timely fashion. Majority of emergency resuscitation drugs can be infused via intraosseous route.22 |
| In neonates and young infants, transdermal absorption may be enhanced due to greater surface area to weight ratio and immature epidermal barrier. Has lead to unintentional toxicities, for example, with iodine or corticosteroids. | Transdermal absorption can be exploited in formulations such as patches (eg, hyoscine, methylphenidate); iontophoretic devices and needleless systems (eg, growth hormone).23 |
| Inhaled medicines target lungs for local effect, but systemic exposure may occur, for example, inhaled corticosteroids can suppress cortisol and affect growth.24 Intranasal route avoids hepatic first-pass metabolism; however, hydrophilic drugs have poor absorption. Diamorphine, midazolam, fentanyl, sumatriptan and desmopressin are used intranasally in children. | Inhalation route can be convenient and effective for a targeted effect. Intranasal administration of drugs has advantages including ease of administration, speed of action, good tolerance; however, it is limited by acceptable volume of administration. |
| Distribution | |
| Body water composition as % body mass in neonates significantly higher than adults (80% vs 60%). Body fat varies through childhood.3 Higher doses of water-soluble drugs (eg, gentamicin) per kg body weight required to reach target concentrations. | |
| Albumin/total protein concentrations lower in neonates but approach adult levels by age of 1. Persistence of foetal albumin for ≤3 months, which has a lower affinity for binding some drugs. Protein binding in neonates reduced by circulating bilirubin and free fatty acids competing for binding sites; increased free drug concentrations leading to pharmacological and adverse effects at lower total drug concentrations. Phenytoin target plasma level range is ∼1/3rd lower in infants <3 months.8 In neonates ceftriaxone displaces protein binding of bilirubin; increased free circulating bilirubin may cross blood–brain barrier and cause brain damage (kernicterus).25 | |
| Metabolism and elimination | |
| Drug metabolism and elimination pathways are immature at birth; drugs commonly have plasma half-lives ≥ 2–3 times longer in neonates vs adults. So while higher volumes of distribution require higher loading doses, lower clearance reduces dosing frequency; for example, penicillins, barbiturates. | |
| Hepatic drug metabolism via CYP450 enzymes is immature at birth; Phase I metabolism (oxidation, reduction, hydrolysis) low in neonates, matures during the first 6 months, exceeds adult rates in childhood and slows during adolescence to adult rates. Phase II metabolism (hydroxylation and conjugation) increases over the first 3 months and matures by 3 years. Delayed hepatic glucuronidation is responsible for ‘grey baby syndrome’ when high-dose intravenous chloramphenicol used in neonates.3 Hepatic metabolism high for some drugs in children <10 years; voriconazole clearance threefold higher in children than adults due to a higher contribution of specific oxidative pathways. Other drugs predominantly metabolised by same pathway (CYP2C9/19), for example, phenytoin, omeprazole and sirolimus show higher clearance in children 2–10 years than in adults.26 | |
| Renal elimination reduced in the first 2 years. In premature neonates is dependent on gestational age due to nephrogenesis and changes in renal blood flow. GFR is 2 to 4 mL/min/1.73 m2 at birth in term infants but may be as low as 0.6 to 0.8 mL/min/1.73 m2 in preterm neonates. GFR increases rapidly during the first 2 weeks rising steadily to adult values at 8 to 12 months.3 | |