WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• There is marked variability among patients with Parkinson's disease (PD) in the rate of progression of status (severity) assessed with a global functional ...score (Unified Parkinson's Disease Rating Scale; UPDRS). It has been hypothesized that there are distinct PD subtypes with different rates of progression.
• Previous studies attempted to quantify the rates of progression for tremor‐dominant and postural instability and gait disorder (PIGD)‐dominant subtypes using only baseline clinical features.
WHAT THIS STUDY ADDS
• We used a nonlinear mixed effects modelling approach to describe the time course of the four cardinal features of PD before and during anti‐parkinsonian treatment.
• Tremor‐dominant and PIGD‐dominant subtypes appear to be different stages of the disease rather than persistent attributes in individual patients and do not explain variability in progression among patients. Tremor progresses more slowly than other cardinal features with and without drug treatment. Postural instability and gait disorder is much less sensitive to the symptomatic effects of levodopa than the other cardinal features.
• We have extended the finding that anti‐parkinsonian treatments have symptomatic and disease‐modifying effects on overall function and demonstrate similar effects on each of the four cardinal features of PD.
AIMS
(i) To describe the progression of the cardinal features of Parkinson's disease (PD); (ii) to investigate whether baseline PD subtypes explain disease progression; and (iii) to quantify the symptomatic and disease‐modifying effects of anti‐parkinsonian treatments.
METHODS
Data were available for 795 PD subjects, initially untreated, followed for up to 8 years. Cardinal features tremor, rigidity, bradykinesia, and postural instability and gait disorder (PIGD) were derived from the total unified Parkinson's disease rating scale (total UPDRS), cognitive status from the mini‐mental status exam score (MMSE) and depression status from the Hamilton depression scale (HAM‐D). Analysis was performed using a nonlinear mixed effects approach with an asymptotic model for natural disease progression. Treatment effects (i.e. symptomatic and disease modifying) were evaluated by describing changes in the natural history model parameters.
RESULTS
Tremor progressed more slowly (half‐time of 3.9 years) than all other motor features (half‐time 2–3 years). The MMSE progression was negligible, while HAM‐D progressed with a half‐time of 5 years. Levodopa had marked symptomatic effects on all features, but low potency for effect on PIGD (ED50 of 1237 mg day−1 compared with 7–24 mg day−1 for other motor and nonmotor features). Other anti‐parkinsonian treatments had much smaller symptomatic effects. All treatments had disease‐modifying effects on the cardinal features of PD. Baseline PD subtypes only explained small differences in disease progression.
CONCLUSIONS
This analysis indicates that tremor progresses more slowly than other cardinal features and that PIGD is less treatment responsive in early PD patients. There was no evidence of baseline PD subtypes as a clinically useful predictor of disease progression rate. Anti‐parkinsonian treatments have symptomatic and disease‐modifying effects on all major features of PD.
Personalizing intravenous busulfan doses to a target plasma concentration at steady state (Css) is an essential component of hematopoietic cell transplantation (HCT). We sought to develop a ...population pharmacokinetic model to predict i.v. busulfan doses over a wide age spectrum (0.1-66 years) that accounts for differences in age and body size.
A population pharmacokinetic model based on normal fat mass and maturation based on postmenstrual age was built from 12,380 busulfan concentration time points obtained after i.v. busulfan administration in 1,610 HCT recipients. Subsequently, simulation results of the initial dose necessary to achieve a target Css with this model were compared with pediatric-only models.
A two-compartment model with first-order elimination best fit the data. The population busulfan clearance was 12.4 L/h for an adult male with 62 kg normal fat mass (equivalent to 70 kg total body weight). Busulfan clearance, scaled to body size-specifically normal fat mass, is predicted to be 95% of the adult clearance at 2.5 years postnatal age. With a target Css of 770 ng/mL, a higher proportion of initial doses achieved the therapeutic window with this age- and size--dependent model (72%) compared with dosing recommended by the U.S. Food and Drug Administration (57%) or the European Medicines Agency (70%).
This is the first population pharmacokinetic model developed to predict initial i.v. busulfan doses and personalize to a target Css over a wide age spectrum, ranging from infants to adults.
Among patients with tuberculosis, rifampin plasma concentrations and sputum conversion rates have been reported to be lower in Africans. Rifampin is a substrate of P-glycoprotein (coded for by the ...ABCB1 gene) and organic anion-transporting polypeptide 1B1 (coded for by SLCO1B1). The objectives were to identify genetic polymorphisms of drug transporters and the transcriptional regulators pregnane X receptor (PXR) and constitutive androstane receptor (CAR) with an impact on rifampin pharmacokinetics in South Africans. Fifty-seven patients with tuberculosis from Cape Town underwent pharmacokinetic sampling during treatment with rifampin, pyrazinamide, isoniazid, and ethambutol. DNA was genotyped for ABCB1, SLCO1B1, PXR, and CAR polymorphisms by using real-time PCR. NONMEM was used for data analysis. The allele frequency of the SLCO1B1 rs4149032 polymorphism was 0.70. Patients heterozygous and homozygous for this polymorphism had reductions in the bioavailability (and, thus, the area under the curve AUC) of rifampin of 18% and 28%, respectively. Simulations showed that increasing the daily rifampin dose by 150 mg in patients with the polymorphism would result in plasma concentrations similar to those of wild-type individuals and reduce the percentage of patients with peak plasma concentrations (Cmax) below 8 mg/liter from 63% to 31%. ABCB1, PXR, and CAR polymorphisms were not associated with differences in rifampin pharmacokinetics. SLCO1B1 rs4149032 was present in most patients and was associated with substantially reduced rifampin exposure. These data suggest that the standard recommended dose of rifampin should be reconsidered for South Africans.
Aims
Thrombocytopenia is among the most important adverse effects of linezolid treatment. Linezolid‐induced thrombocytopenia incidence varies considerably but has been associated with impaired renal ...function. We investigated the pharmacodynamic mechanism (myelosuppression or enhanced platelet destruction) and the role of impaired renal function (RF) in the development of thrombocytopenia.
Methods
The pharmacokinetics of linezolid were described with a two‐compartment distribution model with first‐order absorption and elimination. RF was calculated using the expected creatinine clearance. The decrease platelets by linezolid exposure was assumed to occur by one of two mechanisms: inhibition of the formation of platelets (PDI) or stimulation of the elimination (PDS) of platelets.
Results
About 50% of elimination was found to be explained by renal clearance (normal RF). The population mean estimated plasma protein binding of linezolid was 18% 95% confidence interval (CI) 16%, 20% and was independent of the observed concentrations. The estimated mixture model fraction of patients with a platelet count decreased due to PDI was 0.97 (95% CI 0.87, 1.00), so the fraction due to PDS was 0.03. RF had no influence on linezolid pharmacodynamics.
Conclusion
We have described the influence of weight, renal function, age and plasma protein binding on the pharmacokinetics of linezolid. This combined pharmacokinetic, pharmacodynamic and turnover model identified that the most common mechanism of thrombocytopenia associated with linezolid is PDI. Impaired RF increases thrombocytopenia by a pharmacokinetic mechanism. The linezolid dose should be reduced in RF.
A primary goal of clinical pharmacology is to understand the factors that determine the dose-effect relationship and to use this knowledge to individualize drug dose.
A principle-based criterion is ...proposed for deciding among alternative individualization methods.
Safe and effective variability defines the maximum acceptable population variability in drug concentration around the population average.
A decision on whether patient covariates alone are sufficient, or whether therapeutic drug monitoring in combination with target concentration intervention is needed, can be made by comparing the remaining population variability after a particular dosing method with the safe and effective variability.
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• The marked between variability in the rate of progression of Parkinson's disease severity assessed with a global functional score (Unified Parkinson' ...Disease Rating Scale, UPDRS) is recognized but its origin is uncertain and variously attributed to different subtypes of Parkinson's disease, life style, genetic variability and treatment. An increased risk of death in patients treated with selegiline has been reported but this is controversial.
WHAT THIS STUDY ADDS
• We used a hazard model approach to describe the time to clinical events (death, disability, depression and dementia). The time course of disease status changes was shown to be a key predictor of the risk of these events. Baseline motor subtype was not a predictor of outcome events. Selegiline was associated with an increased risk of death that was independent of its effect on disease status.
AIM To describe the time to clinical events (death, disability, cognitive impairment and depression) in Parkinson's disease using the time course of disease status and treatment as explanatory variables.
METHODS Disease status based on the Unified Parkinson's Disease Rating Scale (UPDRS) and the time to clinical outcome events were obtained from 800 patients who initially had early Parkinson's disease. Parametric hazard models were used to describe the time to the events of interest.
RESULTS Time course of disease status (severity) was an important predictor of clinical outcome events. There was an increased hazard ratio for death 1.4 (95% CI 1.31, 149), disability 2.75 (95% CI 2.30, 3.28), cognitive impairment 4.35 (95% CI 1.94, 9.74), and depressive state 1.43 (95% CI 1.26, 1.63) with each 10 unit increase of UPDRS. Age at study entry increased the hazard with hazard ratios of 49.1 (95% CI 8.7, 278) for death, 4.76 (95% CI 1.10, 20.6) for disability and 90.0 (95% CI 63.3–128) for cognitive impairment at age 60 years. Selegiline treatment had independent effects as a predictor of death at 8 year follow‐up with a hazard ratio of 2.54 (95% CI 1.51, 4.25) but had beneficial effects on disability with a hazard ratio of 0.363 (95% CI 0.132, 0.533) and depression with a hazard ratio of 0.372 (95% CI 0.12, 0.552).
CONCLUSIONS Our findings show that the time course of disease status based on UPDRS is a much better predictor of future clinical events than any baseline disease characteristic. Continued selegiline treatment appears to increase the hazard of death.
Purpose
Drug interactions are of concern when treating patients co-infected with human immunodeficiency virus (HIV) and tuberculosis. Concomitant use of efavirenz (EFV) with the enzyme inducer ...rifampicin might be expected to increase EFV clearance. We investigated the influence of concomitant tuberculosis treatment on the plasma clearance of EFV.
Methods
Fifty-eight patients were randomized to receive their EFV-containing antiretroviral therapy either during or after tuberculosis treatment. Steady-state EFV plasma concentrations (
n
= 209 samples) were measured, 83 in the presence of rifampicin. Data were analyzed using a non-linear mixed effects model, and the model was evaluated using non-parametric bootstrap and visual predictive checks.
Results
The patients had a median age of 32 (range 19–55) years and 43.1% were women. There was a bimodal distribution of apparent clearance, with slow EFV metabolizers accounting for 23.6% of the population and having a metabolic capacity 36.4% of that of the faster metabolizers. Apparent EFV clearance after oral administration in fast metabolizers was 12.9 L/h/70 kg whilst off tuberculosis treatment and 9.1 L/h/70 kg when on tuberculosis treatment. In slow metabolizers, the clearance estimates were 3.3 and 4.7 L/h/70 kg in the presence and absence of TB treatment, respectively. Overall there was a 29.5% reduction in EFV clearance during tuberculosis treatment.
Conclusion
Unexpectedly, concomitant rifampicin-containing tuberculosis treatment reduced apparent EFV clearance with a corresponding increase in EFV exposure. While the reasons for this interaction require further investigation, cytochrome P450 2B6 polymorphisms in the population studied may provide some explanation.
High-dose human recombinant erythropoietin (rEPO) is a promising potential neuroprotective treatment in preterm and full-term neonates with hypoxic-ischemic encephalopathy (HIE). There are limited ...data on the pharmacokinetics of high-dose rEPO in neonates. We examined the effects of body weight, gestation age, global asphyxia, cerebral ischemia, hypothermia and exogenous rEPO on the pharmacokinetics of high-dose rEPO in fetal sheep. Near-term fetal sheep on gestation day 129 (0.87 gestation) (full term 147 days) received sham-ischemia (
= 5) or cerebral ischemia for 30 min followed by treatment with vehicle (
= 4), rEPO (
= 8) or combined treatment with rEPO and hypothermia (
= 8). Preterm fetal sheep on gestation day 104 (0.7 gestation) received sham-asphyxia (
= 1) or complete umbilical cord occlusion for 25 min followed by
infusion of vehicle (
= 8) or rEPO (
= 27) treatment. rEPO was given as a loading bolus, followed by a prolonged continuous infusion for 66 to 71.5 h in preterm and near-term fetuses. A further group of preterm fetal sheep received repeated bolus injections of rEPO (
= 8). The plasma concentrations of rEPO were best described by a pharmacokinetic model that included first-order and mixed-order elimination with linear maturation of elimination with gestation age. There were no detectable effects of therapeutic hypothermia, cerebral ischemia, global asphyxia or exogenous treatment on rEPO pharmacokinetics. The increase in rEPO elimination with gestation age suggests that to maintain target exposure levels during prolonged treatment, the dose of rEPO may have to be adjusted to match the increase in size and growth. These results are important for designing and understanding future studies of neuroprotection with high-dose rEPO.
While
detection rates in adults, adolescents and older children with cystic fibrosis (CF) have increased, the risk of acquiring this fungal pathogen in young children is unknown.
To determine the ...risk and explanatory factors of acquiring
in children with CF by age 5 years.
Cross-sectional analysis of clinical, bronchoalveolar lavage and treatment data from the Australasian Cystic Fibrosis Bronchoalveolar Lavage study was used to identify predictive factors for detecting
at age 5 years. A parametric repeated time-to-event model quantitatively described the risk and factors associated with acquiring
and
from birth until age 5 years.
Cross-sectional analysis found that the number of
eradication courses increased the odds of detecting
at age 5 years (OR 1.61, 95% CI 1.23 to 2.12). The median (IQR) age for the first
positive culture was 2.38 (1.32-3.79) years and 3.69 (1.68-4.74) years for the first
positive culture. The risk of
and
events changes with time after the first year of study entry. It also decreases for
after completing
eradication (HR 0.15, 95% CI 0.00 to 0.79), but increases for
events (HR 2.75, 95% CI 1.45 to 5.41). The risk of acquiring both types of events increases after having had a previous event.
In young children with CF, completing
eradication therapy and previous
events are associated with increased risk of acquiring
.
What is already known about this subject
• Effects of size, renal function, age (postnatal age, gestational age and postmenstrual age) as predictors of vancomycin clearance in premature neonates are ...established, but the relative contribution of each component remains poorly quantified, largely because these variables are closely correlated.
• We have quantified the covariates contributing to vancomycin clearance population parameter variability in order to establish the major covariates required for dosing predictions. Size, standardized using allometric models, was the primary covariate used in our analysis.
What this study adds
• Size explained 49.8%, postmenstrual age 18.2% and renal function 14.1% of clearance variability.
• Descriptors of the relationship between age and clearance in premature neonates vary.
• The use of a variable slope sigmoidal model to describe the relationship between clearance and postmenstrual age predicted an adult clearance of 3.79 l h−1 70 kg−1 (95% confidence interval 2.76, 4.98) from premature neonatal data.
Aim
To identify and quantify factors describing the variability of vancomycin clearance in premature neonates.
Methods
Population pharmacokinetics were estimated (NONMEM) in 214 neonates postmenstrual age (PMA) 30.4 weeks, range 24–34 weeks; postnatal age 11.9 days, range 1–27 days; weight 1.30 kg, range 0.42–2.6 kg using therapeutic drug monitoring data. Covariate analysis included weight, PMA, serum creatinine, use of inotropes or ibuprofen, positive blood culture and respiratory support. A one‐compartment linear disposition model with zero order input and first‐order elimination was used to describe the data (604 observations).
Results
The population estimate for volume of distribution (V) was 39 l 70 kg−1 (coefficient of variation 19.4%). Clearance (CL) increased from 0.897 l h−1 70 kg−1 at 24 weeks PMA to 2.02 l h−1 70 kg−1 by 34 weeks PMA. The between‐subject variability for CL was 18.6% and the between‐occasion variability was 12.2%. The use of ibuprofen reduced clearance, but this effect was attributable to reduced renal function. Overall, 82% of the variability of CL was predictable. Size explained 49.8%, PMA 18.2% and renal function 14.1%. The use of a variable slope sigmoidal model to describe the relationship between clearance and PMA predicted an adult clearance of 3.79 l h−1 70 kg−1 (95% confidence interval 2.76, 4.98).
Conclusions
Size, renal function and PMA are the major contributors to clearance variability in premature neonates. The small (18%) unexplained variability in clearance suggests target concentration intervention is unnecessary if size, age and renal function are used to predict the dose. Extrapolation to an adult clearance from neonatal data is possible using allometric size models and a function describing clearance maturation.
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