Amgen highlights dosing requirements for cinacalcet
Click Here to Manage Email Alerts
An article suggesting thrice weekly doses of cinacalcet could manage certain aspects of bone and mineral metabolism in patients with chronic kidney disease who need treatment with dialysis appeared in Nephrology News and Issues.1
The dosing strategy described therein does not align with the currently approved label for cinacalcet from the FDA and it differs fundamentally from the one used in large clinical trials that established the safety and efficacy of daily oral doses of cinacalcet for the treatment of secondary hyperparathyroidism among patients with chronic kidney disease undergoing dialysis.
In the original phase 3 clinical studies with cinacalcet, initial daily doses of 30 mg were titrated incrementally as needed every three weeks to a maximum daily dose of 180 mg if plasma parathyroid hormone (PTH) levels measured 24 hours after dosing remained above a threshold of 250 pg/mL, if serum calcium concentrations were greater than 7.8 mg/dL and if symptoms of hypocalcemia were absent. The results from these trials led ultimately to the approval of cinacalcet for use clinically by regulatory authorities worldwide.
The results also documented the safety and efficacy of the dose-titration scheme utilized and provided the framework for the recommendations about drug administration and dosing included in current product labeling. The safety and efficacy of alternative dosing strategies for cinacalcet have not been evaluated in well-designed and carefully conducted prospective clinical trials. Accordingly, treatment with cinacalcet using oral doses given three times per week must be recognized as off-label use of an approved therapeutic agent.
Allosteric activator
Cinacalcet is a calcimimetic agent that functions as an allosteric activator of the calcium receptor (CaR). It was the first calcimimetic agent to be approved for use clinically, and it enhances the effect of extracellular calcium ions to activate the CaR, which in turn diminishes the release of PTH from the parathyroid glands and lowers plasma PTH levels.
Cinacalcet is absorbed rapidly from the gastrointestinal tract after oral administration, and the highest drug concentrations in serum are achieved 60 to 90 minutes after single oral doses. Plasma PTH levels decline promptly during the initial 60 minutes after oral dosing, reaching a nadir after 2 to 6 hours. The early decreases in plasma PTH after oral dosing are thought to reflect higher levels of CaR activation as drug levels in serum approach peak values.
After the initial rapid decline, plasma PTH levels subsequently rise from the nadir during the remainder of the daily dosing cycle, often approaching pre-dose values after 24 hours. As such, daily oral doses of cinacalcet produce an oscillating hormone concentration profile for PTH during each day of treatment, a factor that must be considered when interpreting plasma PTH levels in anyone receiving this calcimimetic agent.
Although the terminal half-life of cinacalcet in serum is estimated to be 30 to 40 hours, the initial serum half-life is approximately 6 hours, a finding likely to render alternate-day dosing ineffective. This relatively short, initial half-life likely accounts for the rise in plasma PTH levels beyond 6 to 8 hours after oral dosing, changes that probably reflect lower levels of CaR activation and less robust inhibition of PTH release from the parathyroid glands as the serum levels of cinacalcet decline late in the 24-hour dosing cycle. These pharmacodynamic results reaffirm the need for daily dosing with cinacalcet to effectively lower plasma PTH levels among patients with secondary hyperparathyroidism as documented previously in clinical trials.
The prompt increases in plasma PTH that occur within the first day or 2 after doses are withheld provide further evidence that daily oral doses of cinacalcet are required to achieve and to maintain biochemical control of secondary hyperparathyroidism among those with this clinical disorder.
Lower plasma PTH
A key therapeutic objective in the treatment of secondary hyperparathyroidism is to lower plasma PTH levels and to maintain these within a range considered to favor bone health and to either partially or completely correct the metabolic bone disease of hyperparathyroidism. Among those treated with cinacalcet, small daily doses are used initially with subsequent upward adjustments to the dose as needed to achieve meaningful reductions in plasma PTH. The evidence that supports a once daily oral-dosing strategy for cinacalcet is based upon careful assessments of the pharmacokinetics of the drug after oral administration and the corresponding pharmacodynamic responses as documented by changes in plasma PTH levels and serum calcium concentrations over time.
As PTH levels vary substantially during the interval between daily doses of cinacalcet, the time between drug administration and the collection of blood samples that are used for plasma PTH determinations should be kept as constant as possible to ensure that PTH values can be interpreted consistently during treatment. Such measures were implemented in each of the large, phase 3 clinical trials that led to the regulatory approval of cinacalcet using daily oral doses for the treatment of secondary hyperparathyroidism among patients with CKD who were also receiving dialysis.
In these studies, doses of cinacalcet were given shortly before initiating scheduled dialysis procedures and again at the same clock time on the following day if no dialysis treatment was planned an approach that served not only to standardize the time of day for daily dosing in each patient, but also to impose a consistent time interval of approximately 24 hours between drug administration and blood sampling for PTH determinations in all study participants.
As such, all decisions about adjustments to the dose of cinacalcet and dose titration during these trials and, ultimately, assessments of therapeutic efficacy were based upon plasma PTH levels measured 24 hours after the preceding dose of cinacalcet.
Daily doses
As discussed already, daily dosing with cinacalcet induces cyclical changes in plasma PTH levels in 24 hours. As plasma PTH levels decrease promptly after oral drug administration, PTH determinations obtained only a few hours after dosing will overstate the magnitude of the reductions in PTH achieved, on average, during the interval between doses due to the subsequent rise in PTH levels later in the 24-hour dosing cycle. These observations provide the rationale for the recommendation in product labeling that PTH levels be measured no earlier than 12 hours after the most recent dose of cinacalcet.
In contrast, PTH measurements done near the end of the 24-hour dosing cycle will understate the degree to which PTH levels have been lowered, on average, during the interval between daily doses because the early reductions in PTH that occur soon after drug administration are not apparent. These more conservative assessments of the PTH-lowering effect of cinacalcet were used to guide dosage adjustments during the large phase 3 clinical trials mentioned previously. The safety profile for cinacalcet established in these studies thus can be applied generally to patients who receive daily doses of cinacalcet when treatment is monitored as described, but similar outcomes for safety cannot be extended to other dosing regimens.
To date, none of the published reports that describe clinical and biochemical outcomes among patients given thrice weekly doses of cinacalcet provide information sufficient to establish the temporal relationship between doses of cinacalcet and the collection of blood samples used for PTH determinations. The same limitations apply to the biochemical results used to guide ongoing clinical care by various dialysis providers because blood samples for routine monthly biochemical determinations are not collected with these pharmacodynamic considerations in mind despite the guidance provided in product labeling for cinacalcet. Accordingly, valid comparisons of the relative efficacy of thrice weekly oral doses vs. daily oral doses of cinacalcet for lowering plasma PTH levels among those with secondary hyperparathyroidism cannot be made using currently available data.
Thrice weekly doses
In future studies to assess the safety and efficacy of thrice weekly doses of cinacalcet for the management of secondary hyperparathyroidism in patients on dialysis, the timing of plasma PTH determinations to be used for dosage adjustments during study could be standardized in relation to doses of cinacalcet by using PTH values obtained 48 hours after the preceding dose in manner like that described in earlier clinical trials with daily doses of cinacalcet. It is known, however, that PTH levels measured 48 hours after doses of cinacalcet are substantially higher than levels determined only 24 hours after dosing. Using the higher 48-hour, post-dose values to guide decisions about upward dose titration will introduce bias toward the use of larger doses of cinacalcet. As a result, greater reductions in plasma PTH would be expected to occur in the hours immediately after oral dosing based upon the pharmacodynamic considerations discussed previously, which will lead to correspondingly larger decreases in serum calcium concentration and more frequent episodes of hypocalcemia.
This represents the primary safety concern about the use of thrice weekly doses of cinacalcet to manage secondary hyperparathyroidism among patients receiving dialysis. Careful assessments of the pharmacokinetics of cinacalcet and, more importantly, the pharmacodynamic responses to thrice weekly dosing on plasma PTH levels and serum calcium concentrations are needed before such a dosing strategy can be recommended.
As with any oral medication, adherence to and compliance with prescribed dosing regimens are ongoing sources of concern for clinicians. The gastrointestinal adverse events of nausea and vomiting that are not uncommon and the occurrence of episodes of diarrhea present additional challenges for patients receiving cinacalcet, events that may cause them to discontinue treatment. Although oral dosing overseen directly by staff in dialysis facilities may benefit adherence and compliance, the pharmacokinetics and pharmacokinetics of cinacalcet indicate that such an approach is unlikely to be successful in managing secondary hyperparathyroidism among patients who undergo hemodialysis three times per week.
- Reference:
- Abra G, et al. Neph News & Issues. 2021;36(2),26-27.
- For more information:
- William Goodman, MD, is the U.S. medical lead in nephrology for Amgen Inc., Thousand Oaks, California.
Collapse
Read more about
Click Here to Manage Email Alerts