Corinne Seng Yue

A Review of the Pharmacokinetics of Levothyroxine for the Treatment of Hypothyroidism

Thyroxine hormone has been recognised since the early part of the nineteenth century and levothyroxine has been available since the mid-nineteenth century as a replacement for deficient thyroid hormones. While levothyroxine remains the staple treatment for hypothyroidism even to this day, its optimal use can be challenging. As is often the case with older drugs, the pharmacokinetics of levothyroxine is often under-appreciated or misunderstood and many factors influence the optimal dosing of levothyroxine. This article will review the pharmacokinetics of levothyroxine in the treatment of hypothyroidism and highlight major concepts that should aid both clinicians and researchers.

Pharmacokinetics and potential advantages of a new oral solution of levothyroxine vs. other available dosage forms.

To better understand the pharmacokinetics and potential advantages of a levothyroxine oral solution vs. tablets and soft gel capsules.4 randomized, 2-treatment, single-dose (600 mcg levothyroxine), 2-way crossover bioequivalence studies in 84 healthy subjects were analyzed. Samples were collected before dosing and until 48-72 h post-dose to calculate noncompartmental baseline-adjusted pharmacokinetic parameters: maximum concentration, time to maximum concentration, and area-under-the-concentration-time-curve from 0 to 48 h and from 0 to 2 h.Mean pharmacokinetic parameters (±standard deviation) for tablets, capsules and solution, respectively, were: area-under-the-concentration-time-curve from 0 to 2 h (ng*h/mL)=68.4±32.8, 64.4±24.4, 99.1±22.7; area-under-the-concentration-time-curve from 0 to 48 h (ng*h/mL)=1 632±424, 1 752±445, 1 862±439; maximum concentration (ng/mL)=67.6±20.9, 68.0±15.9, 71.4±16.0; time of maximum concentration (hours)=2.25±0.99, 2.38±1.58, 1.96±1.07. Overall rate and extent of exposure were not statistically different between formulations, but a faster onset of absorption for the solution was suggested (greater area-under-the-concentration-time-curve from 0 to 2 h and faster time to maximum concentration by an average of 30 min).Levothyroxine rate and extent of exposure are similar between tested formulations. The solution appears however to reach systemic circulation quicker as dissolution is not needed before absorption starts. The solutions greater early exposure and a faster time to maximal concentration of around 30 min may be of benefit to minimize drug-food interactions and deserves further investigations.

Successful treatment of lithium toxicity with sodium polystyrene sulfonate: a retrospective cohort study

Context. Lithium (Li) is a first-line treatment for bipolar disorder but has a narrow therapeutic index. Treatment of Li toxicity includes supportive measures and hemodialysis in severe cases, but this modality is not always immediately available. Sodium polystyrene sulfonate (SPS, Kayexalate™), a cation exchanger, has been promising in animal models and human reports to reduce absorption and enhance elimination of Li. Material and methods. A retrospective cohort study was conducted. All cases of chronic Li intoxication were reviewed in two adult-care hospitals from 2000 to 2009. A group comparison and a within-patient comparison were performed to compare the effect of SPS on the median Li half-life (T1/2). For this study, at least three serum Li levels were required for T1/2 calculations. Results. Forty-eight patients met inclusion requirements, 12 of whom had taken SPS. Median Li T1/2 in the treated and control groups was 20.5 and 43.2 hours, respectively (p = 0.0006). In the 12 treated patients, Li T1/2 during SPS was on average 48.9% shorter than without SPS. Furthermore, in one subject in whom urinary Li data were available, Li clearance with SPS was superior to Li renal clearance. Prolonged constipation was noted in one patient whereas mild hypokalemia was noted in six patients treated with SPS. Conclusion. This study shows that SPS reduced Li T1/2 and suggests that SPS is capable of promoting Li elimination in chronic intoxications. These results warrant a prospective trial looking at the use of SPS in the treatment of Li overdose as an adjunct to supportive measures and hemodialysis.

Population Pharmacokinetic and Pharmacodynamic Analysis of Pegloticase in Subjects With Hyperuricemia and Treatment‐Failure Gout

Pegloticase is designed to convert urate into the easily excretable allantoin to treat hyperuricemia in gout. The aim of this analysis was to describe the pharmacokinetics and pharmacodynamics of pegloticase in 40 gout patients. Pegloticase was administered as intravenous infusions every 2 weeks at 4‐ and 8‐mg doses or every 4 weeks at 8‐ or 12‐mg doses for 12 weeks. Serum pegloticase concentrations, plasma urate, and serum antibody response were determined. Population pharmacokinetics and pharmacodynamics analyses were performed. Data were modeled simultaneously, and covariates were investigated (age, gender, race, body weight, ideal body weight, and antibody response). The dosing regimens to maintain uric acid levels below the therapeutic target of 6 mg/dL were then predicted by the model. The pharmacokinetics were best described by a 1‐compartment linear model, while the pharmacodynamics model was fitted as a direct effect of pegloticase on uric acid concentrations with a suppressive maximum effect attributed to drug (Emax) function. Pegloticase suppressed uric acid levels up to 83%. Weight only affected clearance and volume of distribution. No covariates affected pharmacodynamics. Simulation suggests pegloticase administered at 8 mg every 2 or 4 weeks as 2‐hour intravenous infusions will maintain uric acid levels well under 6 mg/dL.

Aluminum toxicokinetics in peritoneal dialysis patients

Context. Despite the risk of aluminum (Al) toxicity in dialysis patients, little is known about its toxicokinetics (TK) in this population. A national contamination of dialysate solutions with Al provided the opportunity to study Al TK in peritoneal dialysis (PD) patients and to better understand the influence of covariates on its disposition. Methods. Al levels in serum and dialysate as well as other laboratory values were collected prospectively from 83 PD patients after correction of Al contamination. Population TK analyses were conducted with NONMEM VI using standard model discrimination criteria. Covariate analyses were also performed using stepwise forward regression followed by backward deletion. Results. After correction of Al exposure, serum levels declined in a biphasic manner, which was captured by the TK model. The TK of Al were best described by a 2-compartment model with linear elimination. Total creatinine clearance was a significant covariate for total clearance (CL). Mean parameter estimates for volume of central compartment (V1), CL, volume of peripheral compartment (V2), volume of distribution at steady-state (Vss), and intercompartmental clearance (Q) were 168 L, 8.99 L/day, 12 000 L, 12 168 L, and 4.93 L/day, respectively. Inter-individual variability for CL and V2 were 22.6 and 51.1%, respectively. Al distributional half-life was 8.5 days, while the terminal elimination half-life was 7.2 years. This model confirms that the large Vss reflects the widespread distribution of Al in bone, lungs, liver, and other tissues. Conclusion. This study describes the first population Al TK model in a large group of PD patients, which includes a covariate effect. The model confirms the extensive half-life and tissue distribution of Al in a dialysis-dependent population.

Performance of different population pharmacokinetic algorithms.

Background: There has been an increased focus on population pharmacokinetics (PK) to improve the drug development process since the “Critical Path paper” by the Food and Drug Administration. This increased interest has given rise to additional algorithms. Objectives: The purpose of this exercise was to compare the new algorithms iterative-2-stage (ITS) and maximum likelihood expectation maximization (MLEM) available in ADAPT 5 with other methods. Methods: A total of 29 clinical trials with different study designs were simulated. Different algorithms were used to fit the simulated data, and the estimated parameters were compared with the true values. The algorithms ITS and MLEM were compared with the standard-2-stage, Iterative-2-Stage (IT2S) method in the IT2S package and the first-order conditional estimate (FOCE) method in NONMEM version VI. Imprecision and bias for the population PK parameters, variances, and individual PK parameters were used to compare the methods. Results: Population PK parameters were well estimated and bias low for all nonlinear mixed effect modeling approaches. These approaches were superior to the standard-2-stage analyses. The algorithm MLEM was better than IT2S and ITS in predicting the PK and variability parameters. Residual variability was better estimated using MLEM and FOCE. A difference in the estimation of the variance exists between FOCE and the other methods. Variances estimated with FOCE often had shrinkage issues, whereas MLEM in ADAPT 5 had practically no shrinkage problems. Using MLEM, a reduction from 3000 to 1000 samples in the expectation maximization step had no impact on the results. Conclusions: The new algorithm MLEM in ADAPT 5 was consistently better than IT2S and ITS in its prediction of PK parameters, variances, and the residual variability. It was comparable with the FOCE method with significantly fewer shrinkage issues in the estimation of variance. The number of samples used in the expectation maximization step with MLEM did not influence the results.

Population pharmacokinetic and pharmacodynamic modeling of acetazolamide in peritoneal dialysis patients and healthy volunteers.

PURPOSE To characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of acetazolamide (ACTZ) in peritoneal dialysis patients, ACTZ 500 mg was administered intravenously to 7 healthy subjects (HV) and 8 peritoneal dialysis patients (CAPD). METHODS Population PK/PD modeling was performed with ACTZ serum (total and unbound), urine and dialysate concentrations, intra-ocular pressure (IOP) and covariates. A multi-compartment PK model (accounting for non-linear protein binding) and an inhibitory Emax (maximal change in IOP) PD model were selected. RESULTS As expected, renal clearance (which almost equals total body clearance) was severely decreased in CAPD (1.2 vs 80.3 L/h) and the elimination half-life of total ACTZ was prolonged (20.6 vs 3.4 hours). The protein binding was significantly altered with a mean free fraction 4.2% in HV and 8.6% in CAPD. Moreover protein binding of ACTZ was concentration dependent in both HV and CAPD. Despite a higher free fraction of ACTZ, the Emax was lower in CAPD: 4.4±1.4 vs 7.4±2.8 mmHg. CONCLUSION Both PK and PD are significantly altered in dialysis patients.

Novel Population Pharmacokinetic Method Compared to the Standard Noncompartmental Approach to Assess Bioequivalence of Iron Gluconate Formulations

PURPOSE Iron-containing products are atypical in terms of their pharmacokinetic properties because iron is only removed by plasma sampling and is non-linear. This study aims to present a novel way of assessing the relative bioavailability of two sodium ferric gluconate complex (SFGC) formulations and compare this approach to a standard previously published noncompartmental approach. METHODS Data were from open-label, randomized, single-dose studies (Study 1 was parallel whereas Study 2 was crossover). Subjects with low but normal iron levels were infused IV SFGC in sucrose by GeneraMedix Inc. and/or Ferrlecit ® Injection (Watson Laboratories Inc.). In Study 1 (n=240), 125 mg was infused over 10 minutes. In Study 2 (n=29), 62.5 mg was infused over 30 minutes. Samples were assayed for total iron (TI) and transferrin-bound iron (TBI) over 36 hours (Study 1) or 72 hours (Study 2) post-dose. Studies 1 and 2 used standard noncompartmental analysis. Study 2 also used population PK (PPK) analyses with ADAPT 5®. The final model predicted SFGC area-under-the-curve (AUCpred) and maximal concentration (Cmaxpred). Analyses of variance was conducted on ln-transformed PK parameters. Ratios of means and 90% confidence intervals (CIs) were estimated. Bioequivalence was demonstrated if values were within 80-125%. RESULTS For Study 1, ratios and 90% CIs for TI baseline-corrected Cmax and AUC0-36 were 100.4 (96.5 - 104.5) and 99.7 (94.2 - 105.5). For TBI, results for TI baseline-corrected Cmax and AUC0-36 were 86.8 (82.7 - 91.1) and 92.4 (85.6 - 99.7). For Study 2, a multi-compartmental model simultaneously described the PK of TI, TBI and SFGC. Ratios and 90% CIs for SFGC Cmaxpred and AUCpred were 89.9 (85.9 - 94.0) and 89.7 (85.7 - 93.9), while ratios and 90% CI obtained from the noncompartmental analysis of Study 2 did not meet BE criteria because of low power. CONCLUSIONS Both the standard and PPK modeling approach suggested bioequivalence between the iron products. However, with the PPK method, less subjects were required to meet study objectives compared to the standard noncompartmental approach which required considerably more subjects (29 vs 240).