Limited sampling model for advanced mycophenolic acid therapeutic drug monitoring after liver transplantation.

BACKGROUND: The immunosuppressive drug mycophenolate mofetil (MMF), with mycophenolic acid (MPA) as active metabolite, is a nonnephrotoxic alternative to calcineurin inhibitors. Therapeutic drug monitoring (TDM) of MPA may improve clinical benefit from MMF therapy, especially in MMF monotherapy or with reduced dose of a calcineurin inhibitor. Limited data are available on TDM strategies for MPA in orthotopic liver transplantation (OLT). The authors here describe the pharmacokinetic (PK) behavior of MPA after OLT and developed a Bayesian limited sampling model for monitoring MMF after OLT. METHODS: PK data were obtained from 57 stable patients, and trapezoidal area under the curve (AUC(0-12h)) was calculated. The effect of the covariates kidney function and serum albumin concentration was studied. A TDM strategy was developed based on individualized population PKs using Bayesian estimations and limited sampling models to predict the MPA AUC. RESULTS: A relationship between MMF dose and MPA AUC was found and a 8-fold apparent clearance range of MPA was observed at the same dose level. Significant relationships of albumin concentration and creatinine clearance with MPA plasma clearance were identified (respectively, r² = 0.12 and 0.24; P < 0.05). A model with limited sampling at 0, 0.5, 1, 2, and 3 hours after drug administration showed very good correlation with trapezoidal AUC(0-12h) with acceptable bias and precision (r² = 0.92, mean prediction error = 1, mean absolute prediction error = 13; P < 0.05). CONCLUSIONS: Remarkable variability of MPA clearance in stable OLT patients exists, which can be partially explained by the patients' albumin serum levels and creatinine clearance. Systemic exposure in these patients can be accurately assessed by the Bayesian limited sampling TDM strategy.

Bisphosphonate therapeutics in bone disease: the hard and soft data on osteoclast inhibition.

Bisphosphonates are chemically stable structural analogs of inorganic pyrophosphate. Owing to their ability to inhibit osteoclast activity, bisphosphonates have become the primary agents to treat conditions marked by excessive osteoclast-mediated bone resorption, such as osteoporosis, Paget's disease of bone, and cancer-associated bone disease. At the molecular level, bisphosphonates exert their anti-resorptive effects by inhibiting farnesyl pyrophosphate synthase activity within osteoclasts. Bisphosphonates are generally well tolerated, with many patients now having been treated for more than ten years. Widespread bisphosphonate use, however, has revealed both short-term and long-term side effects in some patients. Here, we review our current understanding of the mechanisms by which bisphosphonates inhibit osteoclast function, the current roles for these medications in clinical practice, and areas of concern that have emerged with widespread bisphosphonate use.

Bone physiology, disease and treatment: towards disease system analysis in osteoporosis.

Osteoporosis is a chronic progressive disorder and is regarded as an important worldwide health issue. The development of novel treatments and the comparison of the effects of novel and existing treatments in osteoporosis are complicated by the difficulties of establishing drug effects on disease progression, as reflected in the slowly changing primary biomarker, bone mineral density. In recent years, research has considerably improved our understanding of the pathophysiology of osteoporosis. Specifically, various biomarkers have been identified that reflect bone physiology at the cellular level. These biomarkers mirror the dynamics of bone formation and degradation on a shorter timescale than bone mineral density as a composite measure. These markers can therefore, in principle, be used to characterize the underlying regulatory system and to quantify drug effects in osteoporosis. Recently, the concept of disease system analysis has been proposed as a novel approach to characterize, in a strictly quantitative manner, drug effects on disease progression. This approach integrates physiology, disease progression and drug treatment in a comprehensive mechanism-based model, using dynamic information on a network of biomarkers. This review focuses on the use of disease system analysis for the characterization of drug effects on osteoporosis. It is concluded that, although the development of fully mechanistic disease system models may be practically impossible, parsimonious--but mechanism-based--disease system models may ultimately be used to adequately predict the long-term effects of drug treatment on clinical outcomes.

Flexible limited sampling model for monitoring tacrolimus in stable patients having undergone liver transplantation with samples 4 to 6 hours after dosing is superior to trough concentration.

Trough (C0) monitoring is not optimal for therapeutic drug monitoring of tacrolimus. To better estimate systemic exposure of tacrolimus and achieve clinical benefit, an improved therapeutic drug monitoring strategy should be developed. The authors examined which single and combination of time points best estimated the empiric "gold standard" AUC0-12h and developed and validated a new, flexible, and accurate limited sampling model for monitoring tacrolimus in patients having undergone liver transplantation. Twenty-three stable patients with full AUC0-12h were divided into two groups based on area under the concentration-time curve/dose. With multiple regression analysis, limited sampling formulae were derived and population-pharmacokinetic-based limited sampling models were developed and validated. A regression analysis was performed between either area under the concentration-time curves calculated with formulae or models with the reference trapezoidal AUC0-12h. Both formulae and models based on single samples C4-C6 (r2 = 0.94 [MPE/MAPE 0/7]-0.90 [2/8] and 0.97 [0/7]-0.97 [1/5]) showed excellent performance. The calculated area under the concentration-time curve target range for tacrolimus was 90 to 130 h*microg/L. Multiple point sampling performed better, especially when using models (r2 > 0.94). C0 was a less precise predictor of AUC0-12h compared with both formulae and models (r2's 0.68 [5/17] and 0.87 [2/14]). In conclusion, trough concentration monitoring is not an accurate method for assessing systemic exposure to tacrolimus in stable patients having undergone liver transplantation. This new limited sampling model, based on single time points C4-C6, shows excellent performance in estimating the AUC0-12h.

Skeletal retention of bisphosphonate (pamidronate) and its relation to the rate of bone resorption in patients with breast cancer and bone metastases.

UNLABELLED: Bisphosphonate pharmacokinetics may affect individual responses. Skeletal retention of pamidronate infused monthly to patients with bone metastases was highly variable (12-98%) and did not diminish with time, showing the capacity of the skeleton to retain large amounts of bisphosphonate. Relationships between skeletal retention of pamidronate and rate of bone resorption are complex and depend on previous treatment and the total amount of retained bisphosphonate. INTRODUCTION: Bisphosphonates (BPs) given intravenously every 3-4 weeks are effective in the management of metastatic bone disease from breast cancer, but responses among patients vary, and it is not known whether current dose and dose intervals are appropriate for an individual patient. An influence of pharmacokinetics of BPs on antiresorptive action may contribute to this variation in response. To test this hypothesis, we determined the skeletal retention of intravenous pamidronate and its association to the rate of bone resorption in patients with bone metastases from breast cancer. MATERIALS AND METHODS: In a cross-sectional study, 24-h urinary excretion of pamidronate and the biochemical marker of bone resorption N-terminal telopeptide of type 1 collagen and serum alkaline phosphatase were measured in 40 patients with bone metastases from breast cancer at the beginning, after 3-6 months, and after 1 year of treatment with intravenous pamidronate 90 mg every 3-4 weeks. RESULTS AND CONCLUSIONS: Skeletal retention (dose--amount excreted into urine) 2 days after infusion varied between 12% and 98% (mean, 62%) of the administered dose, but there were no differences in retention between patients receiving pamidronate for the first time or after 3-6 months or after 1 year of treatment. Retention of pamidronate was related to the prevalent rate of bone turnover in previously untreated patients, whereas no such relationship was found in previously treated patients. Rate of bone resorption after treatment seemed to be related to the amount of pamidronate retained. During 1 year of treatment, retention of pamidronate remained constant, indicating no saturation of skeletal binding sites with treatment. The variability in retention among individual patients can be attributed to the number of available binding sites. This is related, however, to bone turnover only before the start of treatment. The apparent relationships between skeletal retention and antiresorptive effect could have implications for the design of optimal therapeutic regimens with BPs in patients with bone metastases from breast cancer.

Absorption of the oral bisphosphonate alendronate in osteoporotic patients with Crohn's disease.

The absorption of bisphosphonates from the gut is poor. The question arises whether the absorption of alendronate, and thus its bioavailability, is further altered by the local inflammatory process in patients with Crohn's disease, thereby potentially affecting clinical outcome when used in the treatment of osteoporosis. To address this question, urinary excretion of alendronate was evaluated 3 months and 6 months after start of treatment with oral alendronate at a dose of 10 mg/day in 19 osteoporotic patients with stable Crohn's disease, 12 of whom had an intestinal resection. Biochemical parameters of bone turnover and BMD were also measured at start and at 6 months. Thirteen patients had been previously treated with glucocorticoids and five were currently using them. The average 24-h urinary excretion of alendronate was 0.5-0.6% of the dose administered, a figure comparable to that reported for osteoporotic patients without gut pathology. There was a significant decrease from baseline in urine N-telopeptides of collagen cross-links (NTx)/creatinine (60%) associated with an increase in lumbar spine BMD of already 2% after 6 months of treatment. Our data suggest that in patients with Crohn's disease, alendronate is adequately absorbed from the intestine and retained in the skeleton. This adequacy is confirmed by appropriate suppression of bone resorption and increase in lumbar spine BMD. These data hold significant implications for the clinical management of patients with Crohn's disease and osteoporosis.

Pharmacokinetics/pharmacodynamics of bisphosphonates: use for optimisation of intermittent therapy for osteoporosis.

Bisphosphonates suppress osteoclast-mediated bone resorption and are widely used in the management of osteoporosis. Daily oral administration of alendronic acid and risedronic acid have been shown to reduce the risk of vertebral and non-vertebral fractures. Once-weekly regimens with these bisphosphonates are pharmacologically equivalent to daily regimens. Regimens with treatment-free intervals longer than 1 week present an attractive therapeutic option as they may offer additional patient convenience and long-term adherence to treatment. However, until recently, such regimens, usually referred to as intermittent or cyclical, have not shown any convincing antifracture efficacy in clinical trials, probably because of the empirical manner in which the design of these regimens has been approached. Investigation of pharmacokinetics/pharmacodynamics of bisphosphonates may help in the design of effective intermittent dosage regimens. Bisphosphonates are poorly absorbed from the gastrointestinal tract and about 50% of the absorbed drug is taken up selectively by the skeleton, while the rest is excreted unaltered in urine. Bisphosphonates exert their action at the bone surface, where they are taken up by the osteoclasts during bone resorption. Therefore, when describing the pharmacokinetics of bisphosphonates in relation to the pharmacodynamics, the amount of bisphosphonate at the skeleton should be accounted for. Few of the reported clinical pharmacokinetic studies addressed this issue. This is partly due to the absence of study design elements to account for skeletal binding of the drugs. Pharmacokinetic studies have also been hampered by technical difficulties in determining the concentration of bisphosphonates in serum and urine. Moreover, most clinical pharmacokinetic (but also pharmacokinetic/pharmacodynamic) studies have primarily used noncompartmental analysis, leaving out the distinct advantages of modelling and simulation techniques. Clinically, the primary action of bisphosphonates can be assessed by the measurement of biochemical markers of bone resorption. Recent studies indicate that the pattern of these markers during bisphosphonate treatment may be predictive of antifracture efficacy; however, only limited data are available for the development of pharmacokinetic/pharmacodynamic models that are able to predict the response of these markers to different treatment regimens with bisphosphonates. Recently, pharmacokinetic/pharmacodynamic models for response to bisphosphonates have been described and, at present, some of them are being used in the design of bisphosphonate regimens with long drug-free intervals.

AUC-guided dosing of tacrolimus prevents progressive systemic overexposure in renal transplant recipients.

BACKGROUND: Tacrolimus has a narrow therapeutic window, and bioavailability is known to vary considerably between renal transplant recipients. Most centers still rely on measurement of trough levels, but there are conflicting reports on the correlation between tacrolimus trough levels and systemic exposure, as measured by the area-under-the-concentration-over-time curve (AUC((0-12h))). METHODS: We developed and validated a two-compartmental population-based pharmacokinetic model with Bayesian estimation of tacrolimus systemic exposure. Subsequently, we used this model to apply prospectively AUC-guided dosing of tacrolimus in 15 consecutive renal transplant recipients. The main objective was to study intrapatient variability in the course of time. RESULTS: Bayesian forecasting with a two-point sampling strategy, a trough level, and a second sample obtained between two and four hours post-dose significantly improved the squared correlation with the AUC((0-12h)) (r(2)= 0.94). Compared with trough level monitoring only, this approach reduced the 95%-prediction interval by 50%. The Bayesian approach proved to be feasible in clinical practice, and provided accurate information about systemic tacrolimus exposure in individual patients. In the AUC-guided dosing cohort the apparent clearance of tacrolimus decreased gradually over time, which was not reflected in corresponding trough levels. CONCLUSION: This simple, flexible method provides the opportunity to tailor immunosuppression, and should help minimize tacrolimus-related toxicity, such as nephrotoxicity and post-transplant diabetes mellitus.

Short term whole body retention in relation to rate of bone resorption and cartilage degradation after intravenous bisphosphonate (pamidronate) in rheumatoid arthritis.

OBJECTIVE: Bisphosphonates (BP) inhibit osteoclast-mediated bone resorption, and have been reported to decrease the rate of cartilage degradation. The anti-resorptive effect of BP is determined by the amount of BP retained by the skeleton. In rheumatoid arthritis (RA) the uptake is not confined only to the skeleton, but BP is also retained in joints, which could have implications for dose regimens. We investigated the whole body retention (WBR) of pamidronate and its relationship to bone resorption and cartilage degradation in patients with active RA. METHODS: Twenty-six patients received placebo, 45 mg, or 90 mg intravenous pamidronate. Serum and urine samples were collected before and for 12 days after drug administration. Rate of bone resorption was assessed by the biochemical markers: serum carboxy terminal cross-linked telopeptide of type I collagen, urinary carboxy terminal cross-linked telopeptide of type I collagen normalized to creatinine and urinary amino-terminal telopeptide of type I collagen normalized to creatinine; and rate of cartilage degradation by urinary carboxy terminal telopeptide of type II collagen normalized to creatinine. WBR was derived from urinary excretion of pamidronate data. RESULTS: Pamidronate induced a rapid and sustained decrease in the level of biochemical markers of bone resorption and cartilage degradation. The mean WBR of pamidronate was 69% of the administered dose, and showed a remarkably wide range (41-96%). The decrease in rate of bone resorption, but also rate of cartilage degradation appeared to be related to the WBR of pamidronate. CONCLUSION: This is the first study in which the effect of BP treatment has been studied in relation to the amount of BP retained by the body in patients with active RA. The total amount of BP retained by the body shows a remarkably wide range and is comparable with literature on patients with osteoporosis. The apparent relationships between the amount of BP retained by the body and the effect could have implications for therapeutic regimens in patients with RA.

Switching monitoring of emulsified cyclosporine from trough level to 2-hour level in stable liver transplant patients.

After orthotopic liver transplantation (OLT) many patients use emulsified cyclosporine. Recent data showed that blood levels 2 hours after dosing (C-2) better reflect systemic exposure to the drug (area under the blood concentration time curve) than trough levels (C-0) do. We investigated difference in dosage, creatinine clearance (CrCl), blood pressure (BP), freedom from rejection, and relation of C-2, C-0, and AUC while switching 31 stable patients more than 6 months after OLT from C-0 to C-2 monitoring. With C-0 between 90 and 150 ng/mL we collected 24-hour urine, while blood samples were taken at t = 0, 1, 2, 3, 4, 6, and 8 hours after dosing to measure cyclosporine, creatinine, liver tests, and blood pressure and calculated AUC and CrCl. Target AUC was calculated based on C-0. Then the dose was adjusted to two subsequent C-2 values of 600 ng/mL +/- 15%, the above was repeated, and the differences were assessed. Cyclosporine dose was reduced in 21/31 patients (68%) and remained unchanged in 10/31 patients (32%) after conversion. Mean lowering was 69 mg daily (26.9 %, P < 0.0001). After dose reduction the mean increase of CrCl was 7.93 ml/min (11.6%, P = 0.016). Only systolic and mean morning BP decreased slightly but significantly. C-2 correlated better with AUC0-12 (r2 = 0.75) than C-0 (r2 = 0.64). However, 13/21 patients had a second AUC below target AUC and 2 of these 13 patients developed rejection after conversion to C-2 levels. In conclusion, while C-0 monitoring frequently results in overdosing and more renal dysfunction, C-2 monitoring may lead to episodes of underdosing and rejection. Therefore better ways of monitoring cyclosporine dosing need to be devised.

Determinants of induction and duration of remission of Paget's disease of bone after bisphosphonate (olpadronate) therapy.

Bisphosphonates are the treatment of choice of Paget's disease of bone. For optimal patient care determinants of the induction and duration of remission of the disease after bisphosphonate therapy must be defined. We addressed these issues in a longitudinal study of 157 patients with biochemically active disease (serum alkaline phosphatase activity >120 U/L) treated with the bisphosphonate olpadronate and followed for a median period of 37 months (range 3-162, mean 46 +/- 30). Two different total doses of olpadronate were used: an effective dose (40 mg intravenously given over 5 or 10 consecutive days) and a high dose consisting of the effective dose followed by oral olpadronate 200 mg/day for 15 days. Treatment induced biochemical remission, defined as normalization of serum alkaline phosphatase activity, in 89.2% of the patients. There were no differences between the two treatment regimens. The only independent determinants of induction of remission were baseline serum alkaline phosphatase activity and number of affected bones. In contrast, duration of remission depended on the dose of olpadronate given (high versus effective dose, RR of relapse 0.49, 95% CI 0.27-0.89). Additional independent determinants of relapse were nadir value of serum alkaline phosphatase activity after treatment, number of previous therapies, and number of affected bones. Pain scores decreased with therapy in 88% of patients with pain complaints. Pain scores were significantly related to the probability of relapse (RR1.54, 95% CI 1.04-2.27). In this long-term study of a large cohort of patients with Paget's disease we confirmed the efficacy of olpadronate therapy. In addition, we identified and quantified determinants of the response to bisphosphonate that can help in improving the management of patients with Paget's disease with bisphosphonates.

A compartmental pharmacokinetic model of cyclosporin and its predictive performance after Bayesian estimation in kidney and simultaneous pancreas-kidney transplant recipients.

BACKGROUND: Therapeutic drug monitoring of cyclosporin A (CsA) is an obvious necessity because of its unpredictable absorption and narrow therapeutic window. The use of limited sampling models (LSMs) has improved the estimation of the systemic exposure [area under curve (AUC)] compared with C(0h) monitoring, but these equations are rigid and not reliable in patients with an abnormal absorption profile. We developed and validated a limited sampling (t=0, 2 and 3 h) strategy, based on a compartmental population pharmacokinetic (PK) model for CsA after kidney transplantation alone (KTA) and simultaneous pancreas-kidney transplant (SPKT) recipients, a group of patients with unpredictable absorption kinetics. METHODS: A two-compartment model with lag time and first-order absorption was calculated using a PK software package from data of 20 KTA and SPKT recipients and validated prospectively in 20 KTA and 20 SPKT recipients. Calculated population PK parameters were individualized for each of the remaining 40 patients based on their CsA dosing and on one or a combination of measured CsA blood concentrations using the Bayesian fitting method. AUCs were calculated from individualized PK parameters. AUCs were also calculated using previously published LSMs. Relationships between AUCs calculated by the models and the 'golden standard' AUC (trapezoidal rule) were investigated by Pearson correlation test. RESULTS AND CONCLUSIONS: A population two-compartment model is presented to reliably estimate the CsA AUC in KTA and SPKT recipients. The performance of the model to estimate the AUC is comparable to the performance of two published LSMs in KTA patients, but markedly better in SPKT patients. Combined with Bayesian fitting, the model is very flexible since sampling times are not rigid and can be varied as long as dosing and sampling times are recorded accurately. The model has already proven to be clinically useful and is currently used to further investigate CsA in an integrated pharmacokinetic/pharmacodynamic model.

Relationships between pharmacokinetics and rate of bone turnover after intravenous bisphosphonate (olpadronate) in patients with Paget's disease of bone.

Bisphosphonates are the treatment of choice of Paget's disease, but variable responses have been reported, and despite the availability of potent bisphosphonates, biochemical remission is not achieved in a substantial number of patients. This may, in part at least, be because of the influence of pharmacokinetics of bisphosphonates on their pharmacodynamics. That is the response of bone turnover to treatment. To address this issue, we examined the pharmacokinetics and pharmacodynamics of the bisphosphonate olpadronate given intravenously to 75 patients with Paget's disease, using a specific assay for olpadronate concentrations in serum and urine. The skeletal uptake of olpadronate varied greatly among patients and ranged between 10% and 90% of the administered dose. The two major determinants of skeletal uptake were renal function and prevalent rate of bone turnover. Serum and urinary data were well described by a physiology-based four-compartment pharmacokinetic model that takes into account the distribution of the bisphosphonate in the bone and its subsequent elimination. Bone turnover was suppressed to well within the normal range in virtually all patients. This, together with the absence of resolution of effect during 1 year, does not allow the construction of an adequate integrated pharmacokinetic/pharmacodynamic model. However, the pharmacokinetic model, described for the first time in Paget's disease, can accurately simulate the amount of bisphosphonate delivered to the skeleton with different dose regimens as well as the amount still present in bone after 1 year. Such approaches can lead to improved patient care and individualization of treatment of Paget's disease with bisphosphonates.