Sotalol is generally administered twice daily (BID) because its half-life is approximately 12 hours, but dosing must be adjusted for renal function because elimination occurs through renal clearance. The product labeling includes a boxed warning that sotalol should not be initiated in patients with a QTc >450 msec and that the dose should be reduced or discontinued if the QTc prolongs to ≥500 msec.

For patients with CrCl ≥90 mL/min targeting a maintenance dose of 120 mg every 12 hours, the estimated steady-state maximum concentration (Cmax,ss) was 1,299 ng/mL. A simulated 200-mg loading dose produced an average concentration of 1,420 ng/mL, representing a 9% overshoot. A second 120-mg dose was administered 12 hours later, followed by 120 mg every 12 hours. For patients targeting 80 mg BID, the Cmax,ss was 862 ng/mL, and a 120-mg loading dose was proposed, followed by 80 mg BID.

For patients with CrCl 60–90 mL/min targeting 120 mg every 12 hours, a 240-mg loading dose produced a Cmax of 1,889 ng/mL, compared with a Cmax,ss of 1,800 ng/mL, corresponding to a 5% overshoot. A second 120-mg dose was given 8 hours later, followed by 120 mg every 12 hours. When the target maintenance dose was 80 mg BID, a 160-mg loading dose produced a concentration of 1,271 ng/mL, compared with a Cmax,ss of 1,220 ng/mL, representing a 4% overshoot. The second 80-mg dose was given 8 hours later, followed by 80 mg BID.

For patients with CrCl 30–59 mL/min targeting 120 mg every 12 hours, the simulated loading dose was 220 mg, producing a Cmax of 1,785 ng/mL compared with a Cmax,ss of 1,620 ng/mL, or a 10% overshoot. The second 120-mg dose was delayed until 24 hours after the loading dose, after which 120 mg every 12 hours was continued. When the target maintenance dose was 80 mg, the loading dose was 140 mg, producing a Cmax of 1,138 ng/mL versus a Cmax,ss of 1,090 ng/mL, representing a 4% overshoot. The second 80-mg dose was given 24 hours later, followed by 80 mg every 24 hours.

For patients with CrCl 10–29 mL/min targeting 120 mg, the simulated loading dose was 200 mg, producing a Cmax of 1,706 ng/mL compared with a Cmax,ss of 1,610 ng/mL, corresponding to a 6% overshoot. The second 120-mg dose was administered 48 hours later, followed by 120 mg every 48 hours. For a target maintenance dose of 80 mg, the loading dose was 140 mg, producing a Cmax of 1,196 ng/mL versus a Cmax,ss of 1,090 ng/mL, or a 10% overshoot. The second 80-mg dose was administered 48 hours later, followed by 80 mg every 48 hours.

Thus, the modeled accelerated-loading strategy varied according to renal function. The 160-mg loading dose specifically applied to patients with CrCl 60–90 mL/min targeting 80 mg BID, while patients with more substantial renal impairment (CrCl 30–59 or 10–29 mL/min) received 140-mg loading doses for an 80-mg maintenance target, with the second dose delayed to 24 or 48 hours, respectively. QTc was intended to be monitored during the first and second doses to ensure that QTc prolongation remained acceptable.

The investigators also modeled loading to 120 mg PO BID in patients with normal renal function and developed renal function-specific loading strategies for patients with mild, moderate, and severe renal dysfunction. This was based on the fact that sotalol is primarily eliminated unchanged through the kidneys and its elimination is directly related to glomerular filtration. The study additionally modeled 1-day dose escalation for patients with breakthrough atrial fibrillation, including escalation from 80 mg to 120 mg BID and from 120 mg to 160 mg BID, using an initial IV loading dose followed by appropriately timed oral doses. These escalation strategies were modeled in patients with normal renal function as well as those with mild, moderate, and severe renal impairment.

The study also evaluated a “fall-back” strategy for patients initially loaded to 120 mg PO BID who developed excessive QTc prolongation and therefore needed to return to 80 mg PO BID. Modeling suggested waiting 1 day before reinitiating 80 mg BID in patients with CrCl >60 mL/min, at least 3 days in patients with CrCl <60 to ≥30 mL/min, and 7 days in patients with CrCl <30 to ≥15 mL/min. Thus, this study provides modeling evidence for IV-assisted accelerated sotalol loading and dose escalation across renal function categories, but the regimens described were simulation-based rather than clinical outcome data.

Retrospective chart review and pharmacokinetic simulations

N= 35

In the PK analysis, the model predicted that approximately 5–6 doses of oral sotalol 80 mg BID are required to reach steady-state maximum concentration (Cmax,ss) in a 70-kg patient with normal renal function. The concentration-QTc model used a baseline QTc of 405 msec and evaluated oral sotalol doses of 80, 120, and 160 mg BID. At the 80-mg BID dose, the maximum modeled QTc increase from baseline was approximately 13 msec. Across the range of concentrations corresponding to 80, 120, and 160 mg BID, the maximum QTc increase observed during the IV-to-oral loading simulations was approximately 30 msec, which the authors noted was consistent with FDA clinical pharmacology reviews.

For patients with normal renal function, the investigators developed an accelerated IV loading and titration strategy in which 40 mg IV was infused over 1 hour to target an oral maintenance dose of 80 mg BID. QTc was assessed at the end of the infusion. If the change from baseline QTc (∆QTc) was considered acceptable, using a prespecified example safety criterion of ≤15% increase from baseline, an additional 20 mg IV over 0.5 hour could be administered to target 120 mg BID. If QTc remained acceptable, another 20 mg IV over 0.5 hour could be administered to target 160 mg BID. The IV infusion could be stopped at any point if safety concerns arose.

For patients with renal impairment, the overall accelerated-loading strategy was similar, but oral maintenance doses were administered once daily rather than BID. In patients with mild to moderate renal impairment (GFR 40–60 mL/min), the second IV loading dose was reduced to 10 mg over 0.5 hour, rather than 20 mg over 0.5 hour, to better match the Cmax,ss expected with oral maintenance therapy.

The economic model compared the observed oral sotalol strategy with simulated accelerated IV sotalol loading strategies designed to reduce hospitalization to either 1 day or 2 days. For a 2-day length of stay, the IV sotalol strategy was associated with a mean total cost that was $3,123 lower than oral sotalol (95% CI, −$3,640 to −$2,607). For a 1-day length of stay, the IV strategy was associated with a mean total cost that was $4,820 lower (95% CI, −$5,352 to −$4,288).

Except for pharmacy costs, all other simulated medical cost categories were lower with accelerated IV sotalol loading than with the observed oral sotalol strategy. Overall, the 1-day IV loading model produced lower simulated costs than the 2-day model, reflecting the additional cost savings associated with a shorter hospitalization. The pharmacoeconomic results were based on 1,000 Monte Carlo simulations incorporating uncertainty around the model parameters.