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Thomas Ludden

Publications and source records attributed to Thomas Ludden.

3 recordsLinked to original sources
PubMed2004

Population pharmacokinetic modeling of subcutaneously administered etanercept in patients with psoriasis.

The objective of this paper is to present a population PK model which adequately describes the time-concentration profiles of different doses of ctanercept (Enbrel) administered subcutaneously to subjects with moderate-to-severe psoriasis and to simulate the time courses of concentrations following 50 mg once weekly (QW) dosing. Pharmacokinetic (PK) data from three clinical studies with doses 25 mg QW 25 mg twice weekly (BIW) and 50 mg BIW, were used. A one-compartment model with gender, weight and time covariates on the apparent clearance and weight covariate on the apparent volume of distribution was developed. The population mean of the apparent steady state clearance in males was 0.129 l/h. compared to 0.148 l/h in females. The clearance varied with time being lower in the first 2 weeks of the therapy, increasing sharply during weeks 3-4. and converging gradually after that to its steady state level. The population mean of the apparent volume of distribution also varied with time and was 16.11 during week 1, 20.01 during weeks 2-4 and 22.51 after week 4. The population PK model adequately described the observed concentration-time profiles in subjects with psoriasis. Despite a somewhat different covariate set, the parameter estimates of the population PK model for etanercept are very similar between the psoriasis and rheumatoid arthritis populations. The population PK model was used to simulate the pharmacokinetic profiles after a novel 50 mg QW dosing regimen. The simulations show good agreement with the observed data from 84 subjects participating in a fourth study (50 mg QW dose) used as an external validation set. The simulations of the 50 mg QW and the 25 mg BIW dosing regimens show that there is a significant overlap between the profiles yielding similar steady state exposures with both dosing regimens. The latter is an indication that the respective efficacy and safety profiles after those two dosing regimens are likely to be similar.

Computer Simulation↗
PubMed2004

Are bioequivalence studies of levothyroxine sodium formulations in euthyroid volunteers reliable?

Levothyroxine (LT4) has a narrow therapeutic index. Consequently, precise standards for assessing the bioequivalence of different LT4 products are vital. We examined the methodology that the Food and Drug Administration (FDA) recommends for comparing the bioavailability of LT4 products, as well as three modifications to correct for endogenous, thyroxine (T4) levels, to determine if the methodology could distinguish LT4 products that differ by 12.5%, 25%, or 33%. With no baseline correction for the endogenous T4 pool, differences in administered LT4 doses that differed by 25%-33% could not be detected (450 microg and 400 microg doses versus 600 microg dose, respectively). The three mathematical correction methods could distinguish the doses that differed by 25% and 33%. None of the correction methods could distinguish dosage strengths that differed by 12.5% (450 microg versus 400 microg). Dose differences within this range are known to result in clinically relevant differences in safety and effectiveness. Methods of analysis of bioequivalence data that do not consider endogenous T4 concentrations confound accurate quantitation and interpretation of LT4 bioavailability. As a result, products inappropriately deemed bioequivalent may put patients at risk for iatrogenic hyperthyroidism or hypothyroidism. More precise methods for defining bioequivalence are required in order to ensure that LT4 products accepted as bioequivalent will perform equivalently in patients without the need for further monitoring and retitration of their dose.

Adult↗