Original research
Table 2 Observed change in pH of aciclovir solution in the Easypump II LT 270–27-S elastomeric infusion device during storage at room temperature and subsequent exposure to in-use temperature of 32°C
Observed mean±SD pH and change in mean pH from baseline by concentration Low concentration Intermediate concentration
High concentration
Temperature condition Time (hours)
Observed pH
Δ pH
Observed pH
Δ pH
Observed pH
Δ pH
Room temperature (<20°C)
0
10.11±0.01 10.23±0.04 10.22±0.02 10.08±0.04 9.88±0.02 9.71±0.02 9.50±0.04 9.26±0.06 9.00±0.04 7.28±0.4 6.82±0.02 6.85±0.05
0.00 0.12 0.11
11.03±0.00 11.07±0.01 11.05±0.01 11.04±0.01 10.92±0.04 10.96±0.00 10.75±0.04 10.61±0.04 10.53±0.06 10.56±0.05 10.53±0.06 10.45±0.05
0.00 0.04 0.02 0.01
11.13±0.01 11.26±0.02 11.27±0.01 11.22±0.01 11.22±0.01 11.06±0.02 10.92±0.02 10.82±0.02 10.74±0.01 10.35±0.02 10.18±0.04 9.82±0.08
0.00 0.13 0.14 0.09 0.09
12 24 48 96
−0.03 −0.23 −0.40 −0.61 −0.85 −1.11 −2.83 −3.29 −3.26
−0.11 −0.07 −0.28 −0.42 −0.50 −0.47 −0.50 −0.58
120 168 240 336 344 348 360
−0.07 −0.22 −0.32 −0.39 −0.78 −0.95 −1.31
In-use temperature (32°C)
concentration. For 14 days storage at room temperature aciclovir remained stable in solution (figure 1) with no sign of precipita- tion within the body of the infusers at any of the concentrations tested. At the in-use temperature of 32°C, the low and interme- diate doses retained stability above the 95% cut-off, but there was significant precipitation and consequent loss of stability in the high-dose devices. Due to the lack of degradation of any of the concentrations of aciclovir stored at room temperature, we were unable to calculate a degradation rate which could have been applied to a storage period at 25°C. The mid-range concentration (2400 mg/240 mL) showed no degradation in the 24 hours at 32°C while the low concentration results indicated a low level of degradation (2%) at this temperature for 24 hours. Translating this into clinical practice, continuous IV infusion of aciclovir in the OPAT setting is possible at the usual dose used for HSV encephalitis of 30 mg/kg/24 hours. The concentration range we tested would allow for dosing at a weight range of between 6.7 kg and 80 kg, so incorporating a proportion of the paediatric population as well as adult patients. Significant precipitation (rather than degradation) of aciclovir (figure 2) was observed and confirmed by HPLC analysis during
of aciclovir to guanine. Aciclovir under all other conditions was stable (≥95% remaining) for at least 24 hours.
DISCUSSION Treatment courses with IV aciclovir for severe HSV infection can be prolonged, even when the patient is clinically improved, due to lack of suitable oral treatment options. Typical dosing of IV aciclovir with infusions 8-hourly will usually preclude its use in an OPAT setting. Once-daily continuous infusion would be desirable and could allow OPAT use if aciclovir stability was maintained over the 24-hour infusion. In this study, for the first time, the stability of aciclovir in two elastomeric infusion pumps was tested during 14 days of room temperature storage followed by 24 hours exposure to in-use temperature of 32°C at a low, intermediate and high concentration in accordance with most of the UK NHS YCD requirements. Storage at room tempera- ture was interpreted in line with the European Pharmacopoeia rather than the UK NHS stability testing protocol, which spec- ifies room temperature as 25±2°C. As such, our data are not fully compliant with the UK NHS stability protocol. However, our results importantly show that the suitability of aciclovir delivered via OPAT as a continuous infusion is dependent on the
Figure 2 Percentage of aciclovir remaining during exposure to in-use temperature of 32°C following 14 days (336 hours) storage at room temperature by device and dose (low dose=200 mg/240 mL; intermediate dose=2400 mg/240 mL; high dose=4500 mg/240 mL). The grey band shows 95% CI.
Figure 1 Percentage of aciclovir remaining during room temperature (15–25°C) storage for 14 days (336 hours) by device and dose (low dose=200 mg/240 mL; intermediate dose=2400 mg/240 mL; high dose=4500 mg/240 mL). The grey band shows 95% CI.
Sime FB, et al . Eur J Hosp Pharm 2023; 0 :1–6. doi:10.1136/ejhpharm-2023-003784
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