Pharmaceutical and Therapeutics Committee

Livingstone Tertiary Hospital, Stanford Road, Korsten

Private Bag, Port Elizabeth 6014 • 5605 • REPUBLIC OF SOUTH AFRICA
Tel.: +27 (0)41 405 2167 • Fax: +27 (0)41 405 2575• Website: www.echealth.gov.za
Contact for enquiries: Barbara.koopman@echealth.gov.za
___________________________________________________________________________________________________________________________________________________________________________________________

November 2021

FORMULARY REVIEW: PROLONGED RELEASE TACROLIMUS

(ADVAGRAF®)

For the prophylaxis of organ rejection in renal transplant recipients

Recommendation:

✓ Prolonged release tacrolimus (Advagraf ®) for:

▪ Patients with high intra-patient variability in tacrolimus trough levels

Background and rationale:

Organ transplantation is complex and challenged by low rates of organ donation and
increasing use of organs from older donors. Preventing organ rejection is a lifetime
commitment and requires immunosuppressant therapy. Acute rejection rates have
decreased dramatically since the introduction of calcineurin inhibitors such as tacrolimus with
1-year patient and graft survival rates above 90%, however, this gradually declines. (Banas,
et al., 2020).

Tacrolimus has a narrow therapeutic index. This means that small variations in drug exposure
can have a significant impact on patient outcomes. In addition, tacrolimus has a wide
pharmacokinetic variability in kidney transplant patients. Therapeutic drug monitoring (TDM)
is therefore a necessity. The strong correlation between trough concentration (C0) and
systemic exposure (area under the concentration-time curve over 24 hours [AUC0-24]) allows
individualising the dose by monitoring the C0 as a surrogate marker of exposure
(Venkataramanan, et al., 1995) (Caillard, et al., 2016).

Significant inter- and intra-patient variability in C0 is an independent predictor for graft

rejection if levels are subtherapeutic. Conversely, an increased incidence of adverse effects
and renal toxicity may occur if C0 is too high (Caillard, et al., 2016). Between-patient
differences in pharmacokinetics is mostly explained by the variability in the activity and
expression of cytochrome P-450 metabolising enzymes (CYP3A4 and CYP3A5) and the drug-
transporting protein ABCB1. The inter-patient variation is either caused by genetic
polymorphisms or by induction and/or inhibition by other substances such as drugs. Intra-
patient variability (IPV) in tacrolimus exposure is influenced by several modifiable factors such
as non-adherence, concomitant meal intake, concurrent disease states and drug-drug
interactions (Banas, et al., 2020) (Kuypers, 2020) and it is increasingly clear that high tacrolimus
IPV is associated with poor long-term outcomes such as reduction in renal function, increased
rates of rejection, development of de novo donor specific antibody and graft loss (Leino, et
al., 2019).

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Nonadherence to immunosuppressants is common and reported to range from 23-70% (Dew,
et al., 2007) (Leino, et al., 2019). A systematic review revealed 36% of graft losses were
associated with prior nonadherence and a meta-analysis of ten studies found nonadherence
to increase the risk of graft failure sevenfold compared to adherent patients (Odds Ratio [OR]
7.1; 95% Confidence Interval ([CI] 4.4-11.7; p<0.001) (Butler, et al., 2004). The risk of non-
adherence increases with time after the transplantation (Siegal & Greenstein, 1999) and is
regarded as a preventable cause of late acute rejection, chronic rejection and graft loss
(Butler, et al., 2004). In addition, patient compliance has been shown to correlate with the
number of prescribed medications to be taken daily. In general, renal transplant recipients
have a high pill burden, taking multiple daily doses of numerous medications. In a multivariate
logistic regression analysis (n=278), an increased dosing frequency remained independently
associated with adherence (OR, 0.43; 95% CI, 0.22 to 0.86, for three or four times per day
dosing; OR, 2.35; 95% CI, 1.01 to 5.45, for daily dosing; versus two times per day dosing; P =
0.003) (Weng, et al., 2005). This shows that adherence to post-transplant drug regimens more
than doubles when using a less complex once-daily dosing compared to a twice-daily dosing
regimen. Given the gravity and cost of potential negative health outcomes associated with
nonadherence in this patient population, simplifying the dosing regimen to promote better
adherence should be made a priority.

The National Essential Medicine List Committee (NEMLC) approved the twice-daily
immediate-release tacrolimus in 2017 for the following indications in tertiary institutions in
South Africa:

- Primary therapy in high immunological risk renal allograft recipients

- Renal allograft recipients on ciclosporin who experience steroid resistant acute allograft
rejection

A prolonged release tacrolimus formulation (Advagraf™) would allow for a once daily dosing
and has the potential to improve patient compliance. Extended-release formulations have
also been reported to provide less intra-patient variability of exposure (Wu, et al., 2011). As
better adherence and a lower intra-patient variability are associated with improved long
term outcomes in transplant patients (Shuker, et al., 2016) (Wiebe, et al., 2015), this review
was performed comparing key pharmacokinetic considerations, efficacy, safety, adherence
and cost of the two formulations to determine if addition of Advagraf ™ to the hospital’s
formulary is cost-effective and safe.

PHARMACOKINETICS:

Immediate release tacrolimus formulations contain croscarmellose cellulose which delivers

drug to the stomach and proximal small intestine, resulting in rapid absorption over a small
area of the GI tract. Median time to peak blood concentration is approximately 1 hour after
dosing (Banas, et al., 2020). In contrast, prolonged release tacrolimus is formulated with
ethylcellulose which slows water penetration and forms a protective polymer coating which
slows the dissolution rate. Drug delivery is therefore extended beyond the proximal small
intestine and into the distal small intestine. Peak blood concentrations are reached after
approximately 2 hours post dose (Banas, et al., 2020).

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The differences in absorption profiles result in reduced intra-patient variability of tacrolimus
exposure where stable kidney transplant recipients have been converted from immediate
release tacrolimus (IR-tac) to prolonged release tacrolimus (PR-tac) (Wu, et al., 2011).

Phase I pharmacokinetic (PK) trials among healthy volunteers, comparing the prolonged
release tacrolimus to the immediate-release tacrolimus on a 1:1 mg conversion, have
demonstrated a lower peak concentration (Cmax) and a delayed time to maximum
concentration (Tmax) with the prolonged-release formulation, however, the overall drug
exposure (AUC0-24) was comparable between formulations (Barraclough, et al., 2011) (Banas,
et al., 2020). The lower Cmax of prolonged-release tacrolimus does not appear to impact on
either efficacy or safety of this formulation as Cmax is not considered a major variable affecting
the pharmacodynamics of tacrolimus (Tanzi, et al., 2016).

PK in de novo kidney transplant

In a phase II study, the once-daily tacrolimus formulation was associated with a reduction in
AUC0-24 on day 1 by approximately 30%, leading to an increase in the dose in order to
maintain C0 within target range. AUC0-24 was comparable at day 14 and week 6. Trough
concentrations were similar by day 4 (Wlodarczyk, et al., 2009).

Although not observed in all studies, the mean daily maintenance dose was higher for
tacrolimus once-daily than for the twice-daily formulation at all time points in a phase III
noninferiority study in de novo kidney transplantation. In addition, C0 was significantly lower
at week 1 (12.8 vs. 15.3 ng/ml; P < 0.005) but was comparable thereafter (Kramer, et al., 2010).

PK in stable patients converted from IR-tac to PR-tac

Although there is data to support a 1:1 mg conversion from twice-daily IR-tac to once-daily
PR-tac, with C0 and AUC0-24 being comparable for both formulations (van Hooff, et al., 2012),
some studies report reductions in C0 greater than 20% with up to 50% of patients requiring a
dose increase. In 28.0% of patients, dose requirements increased more than 20%. Dose
adjustments were significantly more pronounced in patients who were switched within the
first 3 months post-transplantation compared to patients who were switched later (de Jonge,
et al., 2010). Close TDM is therefore warranted following conversion between formulations
using the same approach and the same trough levels (Banas, et al., 2020).

EFFICACY & SAFETY:

Yang et al. performed a 24-week prospective, single centre, randomized trial to evaluate
safety and efficacy of switching from twice-daily IR-tac to PR-tac in stable renal patients.
Patients were converted on a 1:1 mg basis. No deaths or graft losses occurred during the
study period. There was no significant difference between the two groups in the incidence
of acute rejection at week 24 despite significantly lower tacrolimus blood levels (still in
therapeutic range). Compliance was similar between groups (Yang, et al., 2015).

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In a systematic review of 6 RCTs and 15 observational studies, the evidence comparing the
relative safety and efficacy of the once-daily versus twice-daily tacrolimus was assessed.
There were no differences in biopsy-proven acute rejection (n=1093; Risk Ratio [RR] =1.24; 95%
CI 1.93-1.65; p=0.15), patient survival (n=1156; RR = 0.99; 95% CI 0.97-1.02; P = 0.55), and graft
survival (n = 1156; RR = 0.99; 95% CI 0.97-1.01; P = 0.67) between the two formulations at 12
months. The authors concluded once-daily tacrolimus was as safe and effective as the twice-
daily tacrolimus up to 12 months after kidney transplant (Ho, et al., 2013).

A more recent systematic review and meta-analysis of 11 randomised controlled trials

comparing efficacy and toxicity across different formulations in kidney transplant patients,
found that the impact on kidney allograft function appears to be comparable between IR-
tac and PR-tac with no differences in renal function, graft survival and patient survival at
different times over 4 years after transplantation (Saengram, et al., 2018).

The safety profile of both IR-tac and PR-tac have been found to be similar with no significant
differences in the incidence of hypertension, diabetes mellitus, hyperlipidaemia and renal
function between the two formulations. Drug-drug interactions are also similar (SIngh, et al.,
2015).

Overall, the prolonged release tacrolimus has a similar safety and efficacy profile to the
twice-daily tacrolimus formulation.

ADDITIONAL ADVANTAGES OF ADVAGRAF™

Intra-patient variability

Wu et al., in an open-label, single-centre, prospective single-arm study, investigated the

change of IPV among stable kidney transplant recipients with conversion from IR-tac to PR-
tac in a 1:1 (mg:mg) daily dosing ratio. After conversion, it was found that the percent
coefficient of variation (%CV) of tacrolimus reduced significantly from 14.0% +/- 7.5% to 8.5%
+/- 5.0% (P < 0.05) (Wu, et al., 2011).

Adherence

PR-tac significantly improved adherence to immunosuppressive therapy versus IR-tac in a

randomized controlled trial using electronic monitoring. The ADMIRAD study enrolled 252
participants. At 6 months after randomisation, 81.5% of the once-daily group and 71.9% of
the twice-daily group were still engaged with their treatment (P = 0.0824). Of those patients
who remained engaged with the regimen, 88.2% of the once-daily group and 78.8% of the
twice-daily group (P = 0.0009) took the prescribed number of daily doses. When the patients
took the twice-daily regimen, missed doses occurred in 11.7% of morning doses and 14.2% of
evening doses (P = 0.0035) (Kuypers, et al., 2013).

In addition to improvement in adherence and IPV, Advagraf™ has the potential to lower the
incidence of new-onset diabetes (56.4% vs. 64.0%), a major concern post renal
transplantation (Silva, et al., 2007).

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Renal function has been evaluated in stable kidney transplant recipients, converted from IR-
tac to PR-tac, with studies reporting both increases and decreases in serum creatinine and
estimated glomerular filtration rate (GFR) when comparing before and after formulation
conversion. However, these changes were not clinically relevant (Caillard, et al., 2016). Two
studies observed a decrease in serum creatinine and an increase in eGFR after conversion.
There was a concomitant decrease in C0, but no significant correlation was found between
the reduced C0 and the improved renal function (Kolonko, et al., 2011) (Tinti, et al., 2010).

COST:

The procurement costs of available tacrolimus formulations is summarised in table 1.

Table 1: Current costs of tacrolimus formulations for 2021

Strength PR-tac (Advagraf™) IR-tac (Prograf™)
Cost per 30 capsules Cost per 30 capsules
0.5mg R136.62 R151.80
1.0mg R271.17 R301.30
5.0mg R1339.29 R1488.10

Currently, approximately 68 patients receive tacrolimus immediate-release every month at

Livingstone Hospital. Over the 2020/2021 financial year, a total of R175 689.27 was spent every
month; each patient receiving an average dose of 7.5mg total daily dose. Although costs have
decreased since last year, converting all patients onto Advagraf™ (at current costs) will produce
a cost savings of R224.25 per patient per month in drug costs alone. This equates to R182 988
savings per year for the current number of patients.

Even if 50% of patients require a dose increase of 20% when converting from IR-tac to PR-tac,
there will be a savings of R17 454 in drug costs.

The costs savings associated with preventing graft rejection by using Advagraf™ have not been
accounted for.

Recommendation:
On the basis of the above evidence, it is recommended to add prolonged release tacrolimus to
the hospital formulary for the prevention of organ rejection in renal transplant patients who
experience high variability in tacrolimus levels on the immediate release formulation. This
recommendation is based on similar clinical efficacy and safety profiles between the two
formulations, slightly reduced cost and potentially better long-term outcomes.

Compiled by:

Jo-Anne Becker
Livingstone Hospital Pharmacy Department

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