Obesity is associated with many physiological changes. We review available evidence regarding five commonly accepted assumptions to a priori predict the impact of obesity on drug pharmacokinetics ...(PK).
The investigated assumptions are: 1) lean body weight is the preferred descriptor of clearance and dose adjustments; 2) volume of distribution increases for lipophilic, but not for hydrophilic drugs; 3) CYP-3A4 activity is suppressed and UGT activity is increased, implying decreased and increased dose requirements for substrates of these enzyme systems, respectively; 4) glomerular filtration rate is enhanced, necessitating higher doses for drugs cleared through glomerular filtration; 5) drug dosing information from obese adults can be extrapolated to obese adolescents.
Available literature contradicts, or at least limits the generalizability, of all five assumptions. Clinical studies should focus on quantifying the impact of duration and severity of obesity on drug PK in adults and adolescents, and also include oral bioavailability and pharmacodynamics in these studies. Physiologically based PK approaches can be used to predict PK changes for individual drugs but can also be used to define in general terms based on patient characteristics and drug properties, when certain assumptions can or cannot be expected to be systematically accurate.
ABSTRACT
Purpose
To explore different allometric equations for scaling clearance across the human life-span using propofol as a model drug.
Methods
Data from seven previously published propofol ...studies ((pre)term neonates, infants, toddlers, children, adolescents and adults) were analysed using NONMEM VI. To scale clearance, a bodyweight-based exponential equation with four different structures for the exponent was used: (I) 3/4 allometric scaling model; (II) mixture model; (III) bodyweight-cut-point separated model; (IV) bodyweight-dependent exponent model.
Results
Model I adequately described clearance in adults and older children, but overestimated clearance of neonates and underestimated clearance of infants. Use of two different exponents in Model II and Model III showed significantly improved performance, but yielded ambiguities on the boundaries of the two subpopulations. This discontinuity was overcome in Model IV, in which the exponent changed sigmoidally from 1.35 at a hypothetical bodyweight of 0 kg to a value of 0.56 from 10 kg onwards, thereby describing clearance of all individuals best.
Conclusions
A model was developed for scaling clearance over the entire human life-span with a single continuous equation, in which the exponent of the bodyweight-based exponential equation varied with bodyweight.
In order to characterize the variation in pharmacokinetics of paracetamol across the human age span, we performed a population pharmacokinetic analysis from preterm neonates to adults with specific ...focus on clearance. Concentration‐time data obtained in 220 neonates (post‐natal age 1–76 days, gestational age 27–42 weeks), infants (0.11–1.33 yrs), children (2–7 yrs) and adults (19–34 yrs) were analyzed using NONMEM 7.2. In the covariate analysis, linear functions, power functions, and a power function with a bodyweight‐dependent exponent were tested. Between preterm neonates and adults, linear bodyweight functions were identified for Q2, Q3, V1, V2, and V3, while for CL a power function with a bodyweight‐dependent exponent k was identified (CLi = CLp × (BW/70)k). The exponent k was found to decrease in a sigmoidal manner with bodyweight from 1.2 to 0.75, with half the decrease in exponent reached at 12.2 kg. No other covariates such as age were identified. A pharmacokinetic model for paracetamol characterizing changes in pharmacokinetic parameters across the pediatric age‐range was developed. Clearance was found to change in a nonlinear manner with bodyweight. Based on the final model, dosing guidelines are proposed from preterm neonates to adolescents resulting in similar exposure across all age ranges.
Allometric scaling on the basis of bodyweight raised to the power of 0.75 (AS0.75) is frequently used to scale size-related changes in plasma clearance (CL
p
) from adults to children. A systematic ...assessment of its applicability is undertaken for scenarios considering size-related changes with and without maturation processes. A physiologically-based pharmacokinetic (PBPK) simulation workflow was developed in R for 12,620 hypothetical drugs. In scenario one, only size-related changes in liver weight, hepatic blood flow, and glomerular filtration were included in simulations of ‘true’ paediatric CL
p
. In a second scenario, maturation in unbound microsomal intrinsic clearance (CL
int,mic
), plasma protein concentration, and haematocrit were also included in these simulated ‘true’ paediatric CL
p
values. For both scenarios, the prediction error (PE) of AS0.75-based paediatric CL
p
predictions was assessed, while, for the first scenario, an allometric exponent was also estimated based on ‘true’ CL
p
. In the first scenario, the PE of AS0.75-based paediatric CL
p
predictions reached up to 278 % in neonates, and the allometric exponent was estimated to range from 0.50 to 1.20 depending on age and drug properties. In the second scenario, the PE sensitivity to drug properties and maturation was higher in the youngest children, with AS0.75 resulting in accurate CL
p
predictions above 5 years of age. Using PBPK principles, there is no evidence for one unique allometric exponent in paediatric patients, even in scenarios that only consider size-related changes. As PE is most sensitive to the allometric exponent, drug properties and maturation in younger children, AS0.75 leads to increasingly worse predictions with decreasing age.
Children differ from adults in their response to drugs. While this may be the result of changes in dose exposure (pharmacokinetics PK) and/or exposure response (pharmacodynamics PD) relationships, ...the magnitude of these changes may not be solely reflected by differences in body weight. As a consequence, dosing recommendations empirically derived from adults dosing regimens using linear extrapolations based on body weight, can result in therapeutic failure, occurrence of adverse effect or even fatalities. In order to define rational, patient-tailored dosing schemes, population PK–PD studies in children are needed. For the analysis of the data, population modelling using non-linear mixed effect modelling is the preferred tool since this approach allows for the analysis of sparse and unbalanced datasets. Additionally, it permits the exploration of the influence of different covariates such as body weight and age to explain the variability in drug response. Finally, using this approach, these PK–PD studies can be designed in the most efficient manner in order to obtain the maximum information on the PK–PD parameters with the highest precision. Once a population PK–PD model is developed, internal and external validations should be performed. If the model performs well in these validation procedures, model simulations can be used to define a dosing regimen, which in turn needs to be tested and challenged in a prospective clinical trial. This methodology will improve the efficacy/safety balance of dosing guidelines, which will be of benefit to the individual child.
Purpose
Despite being off-label, intravenous paracetamol (PCM) is increasingly used to control mild-to-moderate pain in preterm neonates. Here we aim to quantify the maturation of paracetamol ...elimination pathways in preterm neonates born below 32 weeks of gestation.
Methods
Datasets after single dose (rich data) or multiple doses (sparse data) of intravenous PCM dose (median (range)) 9 (3–25) mg/kg were pooled, containing 534 plasma and 44 urine samples of PCM and metabolites (PCM–glucuronide, PCM–sulfate, PCM–cysteine, and PCM–mercapturate) from 143 preterm neonates (gestational age 27.7 (24.0–31.9) weeks, birthweight 985 (462–1,925) g, postnatal age (PNA) 5 (0–30) days, current weight 1,012 (462–1,959) g. Population pharmacokinetic analysis was performed using NONMEM® 7.4.
Results
For a typical preterm neonate (birthweight 985 g; PNA 5 days), PCM clearance was 0.137 L/h, with glucuronidation, sulfation, oxidation and unchanged renal clearance accounting for 5.3%, 73.7%, 16.3% and 4.6%, respectively. Maturational changes in total PCM clearance and its elimination pathways were best described by birthweight and PNA. Between 500–1,500 g birthweight, total PCM clearance increases by 169%, with glucuronidation, sulfation and oxidation clearance increasing by 347%, 164% and 164%. From 1–30 days PNA for 985 g birthweight neonate, total PCM clearance increases by 167%, with clearance via glucuronidation and oxidation increasing by 551%, and sulfation by 69%.
Conclusion
Birthweight and PNA are the most important predictors for maturational changes in paracetamol clearance and its glucuronidation, sulfation and oxidation. As a result, dosing based on bodyweight alone will not lead to consistent paracetamol concentrations among preterm neonates.
Drug clearance in obese subjects varies widely among different drugs and across subjects with different severity of obesity. This study investigates correlations between plasma clearance (CLp) and ...drug- and patient-related characteristics in obese subjects, and evaluates the systematic accuracy of common weight-based dosing methods. A physiologically-based pharmacokinetic (PBPK) modeling approach that uses recent information on obesity-related changes in physiology was used to simulate CLp for a normal-weight subject (body mass index BMI = 20) and subjects with various severities of obesity (BMI 25–60) for hypothetical hepatically cleared drugs with a wide range of properties. Influential variables for CLp change were investigated. For each drug and obese subject, the exponent that yields perfect allometric scaling of CLp from normal-weight subjects was assessed. Among all variables, BMI and relative changes in enzyme activity resulting from obesity proved highly correlated with obesity-related CLp changes. Drugs bound to α1-acid glycoprotein (AAG) had lower CLp changes compared to drugs bound to human serum albumin (HSA). Lower extraction ratios (ER) corresponded to higher CLp changes compared to higher ER. The allometric exponent for perfect scaling ranged from -3.84 to 3.34 illustrating that none of the scaling methods performed well in all situations. While all three dosing methods are generally systematically accurate for drugs with unchanged or up to 50% increased enzyme activity in subjects with a BMI below 30 kg/m
2
, in any of the other cases, information on the different drug properties and severity of obesity is required to select an appropriate dosing method for individuals with obesity.
Graphical Abstract
Assessing pain in mechanically ventilated critically ill patients is a great challenge. There is a need for an adequate pain measurement tool for use in conscious sedated patients because of their ...questionable communicative abilities. In this study, we evaluated the use of the Behavioral Pain Scale (BPS) in conscious sedated patients in comparison with its use in deeply sedated patients, for whom the BPS was developed. Additionally, in conscious sedated patients, the combination of the BPS and the patient-rated Verbal Rating Scale (VRS-4) was evaluated.
We performed a prospective evaluation study in 80 nonparalyzed critically ill adult intensive care unit patients. Over 2 mo, nurses performed 175 observation series: 126 in deeply sedated patients and 49 in conscious sedated patients. Each observation series consisted of BPS ratings (range 3-12) at 4 points: at rest, during a nonpainful procedure, at retest rest, and during a routine painful procedure. Patients in the conscious sedated state also self-reported their pain using the 4-point VRS-4.
BPS scores during painful procedures were significantly higher than those at rest, both in deeply sedated patients (5.1 4.8-5.5 vs 3.4 3.3-3.5, respectively) and conscious sedated patients (5.4 4.9-5.9 vs 3.8 3.5-4.1, respectively) (mean 95% confidence interval). For both groups, scores obtained during the nonpainful procedure and at rest did not significantly differ. There was a strong correlation between nurses' BPS ratings and conscious sedated patients' VRS-4 ratings during the painful procedure (r(s) = 0.67, P < 0.001). At rest and during nonpainful procedures, 98% of the observations were rated as acceptable pain (VRS 1 or 2) by both nurses and patients. During painful procedures, nurses rated the pain higher than patients did in 16% of the observations and lower in 12% of the observations.
The BPS is a valid tool for measuring pain in conscious sedated patients during painful procedures. Thus, for noncommunicative and mechanically ventilated patients, it may be regarded as a bridge between the observational scale used by nurses and the VRS-4 used by patients who are able to self-report pain.
Model validation procedures are crucial when models are to be used to develop new dosing algorithms. In this study, the predictive performance of a previously published paediatric population ...pharmacokinetic model for morphine and its metabolites in children younger than 3 years (original model) is studied in new datasets that were not used to develop the original model.
Six external datasets including neonates and infants up to 1 year were obtained from four different research centres. These datasets contained postoperative patients, ventilated patients and patients on extracorporeal membrane oxygenation (ECMO) treatment. Basic observed versus predicted plots, normalized prediction distribution error analysis, model refitting, bootstrap analysis, subpopulation analysis and a literature comparison of clearance predictions were performed with the new datasets to evaluate the predictive performance of the original morphine pharmacokinetic model.
The original model was found to be stable and the parameter estimates were found to be precise. The concentrations predicted by the original model were in good agreement with the observed concentrations in the four datasets from postoperative and ventilated patients, and the model-predicted clearances in these datasets were in agreement with literature values. In the datasets from patients on ECMO treatment with continuous venovenous haemofiltration (CVVH) the predictive performance of the model was good as well, whereas underprediction occurred, particularly for the metabolites, in patients on ECMO treatment without CVVH.
The predictive value of the original morphine pharmacokinetic model is demonstrated in new datasets by the use of six different validation and evaluation tools. It is herewith justified to undertake a proof-of-principle approach in the development of rational dosing recommendations - namely, performing a prospective clinical trial in which the model-based dosing algorithm is clinically evaluated.
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