Info for CFs on Kalydeco

I came across the document below and thought it was useful as I was not sure how much fat to have and the possible food options. I have heard that people have been told varying amounts between 10 and 20g, but there is no official amount in the prescribing information. I believe it is likely the amount of fat needed would vary slightly from person to person depending on their digestion, absorption and drug metabolism. I have often been taking it with 15g of fat through two slices of cheese, with excellent FEV1/symptom changes. The document below suggests 20g, however recently one of the principle investigators from the phase 3 trial said they believe 10g is sufficient.

I read recently that the fat increases the exposure by approximately 2-4 times. Exposure is the area under the curve or basically the level in your blood over the twelve hours. The October Vertex investor presentation mentioned that the absorption of Kalydeco/VX809 varies between CFs due to poor digestion, so given that we don’t have much control over this it is very important to have it with fat.

For anyone who is interested in more pharmacokinetics, the half life of Kalydeco is 12 hours and the T max is 4 hours on average (with food). This means the max dose in your blood is seen after 4 hours, and by 12 hours this max dose has halved. This means if a tablet is missed, there is still Kalydeco in your blood stream until you have your next tablet (but it will be a lower amount). It takes 3-5 days of Kalydeco to reach a steady amount in your blood stream.

I have copied part of the Kalydeco prescribing info as I have noticed this comes up frequently on facebook. It is quite complex, the blue text is a brief summary:

CYP3A are enzymes that metabolise drugs such as Kalydeco. This means that it Kalydeco is taken with a CYP3A inhibitor it will take longer to metabolise Kalydeco and clear from your body, so the dosage may need to be decreased. Inducers increase CYP3A enzyme activity, so Kalydeco will be metabolised faster which may decrease how well Kalydeco works. Other drugs also metabolised by CYP3A may have higher levels if Kalydeco is present.

Inhibitors of CYP3A: Ivacaftor is a sensitive CYP3A substrate. Co-administration with ketoconazole, a strong CYP3A inhibitor, significantly increased ivacaftor exposure [measured as area under the curve (AUC)] by 8.5-fold. Therefore, a reduction of the KALYDECO dose to 150 mg twice-a-week is recommended for co-administration with strong CYP3A inhibitors, such as ketoconazole, itraconazole, posaconazole, voriconazole, telithromycin, and clarithromycin. Co-administration with fluconazole, a moderate inhibitor of CYP3A, increased ivacaftor exposure by 3-fold. Therefore, a reduction of the KALYDECO dose to 150 mg once daily is recommended for patients taking concomitant moderate CYP3A inhibitors, such as fluconazole and erythromycin. Co-administration of KALYDECO with grapefruit juice, which contains one or more components that moderately inhibit CYP3A, may increase exposure of ivacaftor. Therefore, food containing grapefruit or Seville oranges should be avoided during treatment with KALYDECO.

Inducers of CYP3A: Co-administration with rifampin, a strong CYP3A inducer, significantly decreased ivacaftor exposure (AUC) by approximately 9-fold. Therefore, co-administration with strong CYP3A inducers, such as rifampin, rifabutin, phenobarbital, carbamazepine, phenytoin, and St. John’s Wort is not recommended.

CYP3A and/or P-gp Substrates: Ivacaftor and its M1 metabolite have the potential to inhibit CYP3A and P-gp. Co-administration with midazolam, a sensitive CYP3A substrate, increased midazolam exposure 1.5-fold, consistent with weak inhibition of CYP3A by ivacaftor. Administration of KALYDECO may increase systemic exposure of drugs which are substrates of CYP3A and/or P-gp, which may increase or prolong their therapeutic effect and adverse events. Therefore, caution is recommended when co-administering KALYDECO with CYP3A and/or P-gp substrates, such as digoxin, cyclosporine, and tacrolimus.

The FDA have a comprehensive list of medications that can interact to varying degrees with Kalydeco. I am on medications listed here but my dose has not been changed, so check with your doctor. The source is the FDA so I believe the information is accurate:

Table 5.  Classification of In Vivo Inhibitors of CYP Enzymes (CYP3A row)

Strong Inhibitors: Boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole
Moderate inhibitors: Amprenavir, aprepitant, atazanavir, ciprofloxacin, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, imatinib, verapamil
Weak inhibitors: Alprazolam, amiodarone, amlodipine, atorvastatin, bicalutamide, cilostazol, cimetidine, cyclosporine, fluoxetine, fluvoxamine, ginkgo, goldenseal, isoniazid, nilotinib, oral contraceptives, ranitidine, ranolazine, tipranavir/ritonavir, zileuton

Table 6.  Classification of In Vivo Inducers of CYP Enzymes (CYP3A row)

Strong Inducers: Avasimibe, carbamazepine, phenytoin, rifampin, St. John’s wort
Moderate Inducers: Bosentan, efavirenz, etravirine, modafinil, nafcillin
Weak Inducers: Amprenavir, aprepitant, armodafinil, echinacea, pioglitazone, prednisone, rufinamide

This is a link to a medication checker, you can add all your medications to a list and it will tell you if any interact (many of mine do but my Kalydeco dose did not need to be changed, check with your doctor): http://reference.medscape.com/drug-interactionchecker